Malinovska 2013

BBAPAP-38972; No.
of pages: 14; 4C: 8, 9, 10

Biochimica et Biophysica Acta xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Biochimica et Biophysica Acta

journal homepage: www.elsevier.com/locate/bbapap
Protein disorder, prion propensities, and self-organizing macromolecular collectives☆

Liliana Malinovska, Sonja Kroschwald, Simon Alberti ⁎
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307 Dresden, Germany
a r t i c l e i n f o a b s t r a c t
Article history: Eukaryotic cells are partitioned into functionally distinct self-organizing compartments. But while the biogenesis
Received 16 November 2012 of membrane-surrounded compartments is beginning to be understood, the organizing principles behind large
Received in revised form 12 December 2012 membrane-less structures, such as RNA-containing granules, remain a mystery. Here, we argue that protein
Accepted 3 January 2013
disorder is an essential ingredient for the formation of such macromolecular collectives. Intrinsically disordered
Available online xxxx
regions (IDRs) do not fold into a well-defined structure but rather sample a range of conformational states,
Keywords:
depending on the local conditions. In addition to being structurally versatile, IDRs promote multivalent and tran-
Protein disorder sient interactions. This unique combination of features turns intrinsically disordered proteins into ideal agents to
Self-organization orchestrate the formation of large macromolecular assemblies. The presence of conformationally flexible regions,
Phase transition however, comes at a cost, for many intrinsically disordered proteins are aggregation-prone and cause protein
Prion misfolding diseases. This association with disease is particularly strong for IDRs with prion-like amino acid com-
Amyloid position. Here, we examine how disease-causing and normal conformations are linked, and discuss the possibil-
ity that the dynamic order of the cytoplasm emerges, at least in part, from the collective properties of intrinsically
disordered prion-like domains. This article is part of a Special Issue entitled: The emerging dynamic view of
proteins: Protein plasticity in allostery, evolution and self-assembly.
© 2013 Elsevier B.V. All rights reserved.
1. Introduction of a new thermodynamic equilibrium. In dynamic self-assembly,

the structure is resulting from a steady state, which is dynamically
1.1. Bringing order to the cytoplasm maintained by dissipative processes. Dynamic structures are character-
istic of biological systems and are also known as self-organized [1–4].
Living matter is staggeringly complex. Nothing epitomizes this better They are typically very robust and able to self-repair in response to
than the highly organized structure of the cytoplasm. The cytoplasm of even severe perturbations. Being decentralized and only reliant on
eukaryotic cells is a complex landscape, permeated by a fibrous mesh- the collective properties of their components, self-assembly and
work of cytoskeletal proteins and compartmentalized into numerous self-organization are simple but also very efficient ways of achieving
organelles and subcellular domains. What determines the shapes and cellular organization.
sizes of these structures, why they form in particular locations, and In principle, a self-organizing biological system has to fulfill only two
how their architecture affects cellular function is largely unknown. requirements: it has to be dynamic to allow the continuous exchange of
Despite its complex appearance, however, the cytoplasm is organized material and it has to be able to establish and maintain a stable config-
by only one process: molecular self-assembly. uration from initially disordered components. Large macroscopic struc-
A biological structure is self-assembling if it is able to determine its tures, such as mitochondria, the endoplasmic reticulum, or the Golgi,
own organization based on the interactions between its constituent rely on delimiting membranes to maintain their self-organized state.
components. Thus, the intrinsic properties of these components – their To manage a constant flux of material and retain their integrity over
abilities to associate or their affinities for membranes – are the only long timescales, they employ the same mechanisms of protein sorting
factors that determine the final architecture of a self-assembling system. and retrieval. However, despite the importance of membranes in shap-
A system of disordered components can self-assemble into either static ing the overall architecture of eukaryotic cells, they are not essential for
or dynamic structures. In static self-assembly, the structure is the product compartmentalization. Here, we focus on alternative mechanisms for
cellular organization that operate in the absence of membranes.
Abbreviations: IDP, intrinsically disordered protein; IDR, intrinsically disordered re- Numerous membrane-less compartments have been identified, and
gion; PrD, prion domain; IPOD, insoluble protein deposit; JUNQ, juxtanuclear protein with rising interest their number is likely to increase (Table 1). Exam-
quality control; RNP, ribonucleoprotein ples of such compartments include centrosomes, inclusion bodies, and
☆ This article is part of a Special Issue entitled: The emerging dynamic view of pro-
teins: Protein plasticity in allostery, evolution and self-assembly.
cytoplasmic RNP granules. Large membrane-free structures, however,
⁎ Corresponding author. Tel.: +49 351 210 2663; fax: +49 351 210 1209. are not limited to the cytoplasm. They have also been observed in the
E-mail address: alberti@mpi-cbg.de (S. Alberti). nucleus, with nucleoli, Cajal bodies, and PML bodies as prominent
1570-9639/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.bbapap.2013.01.003
Please cite this article as: L. Malinovska, et al., Protein disorder, prion propensities, and self-organizing macromolecular collectives..., Biochim.
Biophys. Acta (2013), http://dx.doi.org/10.1016/j.bbapap.2013.01.003
2 L. Malinovska et al. / Biochimica et Biophysica Acta xxx (2013) xxx–xxx
Table 1
Nuclear and cytoplasmic protein and RNA bodies.
Name Other names Localization Function/description Reference
Cytoplasmic Processing GW (glycine and Cytoplasm of somatic cells Assemble under stress; store translationally silenced and [8,11,15,32,34]
bodies bodies (PBs) tryptophan-rich) bodies, degrade decay-prone mRNA
Dcp-containing bodies
Stress Cytoplasm of somatic cells Form under stress; keep mRNAs of housekeeping [6,10,19]
granules genes paused in translation initiation
(SGs)
EGP bodies Cytoplasm of somatic cells Intermediate between PBs and polysomes; remodel [14]
degradative mRNPs from PBs into translational
mRNPs en route to translation initiation
Germ cell Nuage, Drosophila In the cytoplasm of germ cells, Partitioned to prospective germ cells where they [18,27]
granules melanogaster: Polar granules associated with nuclear envelope direct the timing of nascent maternal mRNA translation;
or Sponge bodies, probably needed for developmental progression
Caenorhabditis elegans: P
granules, mammals:
inter-mitochondrial
cement, or chromatoid body in
spermatocytes
Neuronal Neuronal RNA granules, In the cytoplasm of neurons Transport granules that store translationally repressed [7,26]
transport Dendritic P-body like struc- mRNA (also rRNA) to prevent translation and decay of
granules tures (dIP-bodies), FMRP mRNA until delivered to specific sites
granules, Staufen granules
Metabolic Purinosomes Cytoplasm of somatic cells Protein storage granules in the quiescent state that [5,28,39]
bodies serve as reservoirs for reentry into cell cycle when
nutrients are available again
Actin bodies Cytoplasm of somatic cells Store reorganized F-actin network components in the [30]
quiescence phase, which, like in metabolic bodies, can be
used for F-actin formation after cell-cycle reentry
JUNQ/IPOD = In the yeast cytoplasm in proximity to Storage of soluble ubiquitinated misfolded proteins in [37]
Inclusion the nucleus (JUNQ) and located in the juxtanuclear compartments (JUNQ) and terminally
bodies peripheral perivacuolar location (IPOD) aggregated proteins in peripheral inclusions (IPOD)
Proteasome Proteasome Cytoplasmic storage reservoirs that are [21]
storage mobilized upon exit from quiescent state
granules
Aggresomes Associated with microtubule organizing Forms when proteasome's degradative capacity is [17]
center exceeded
Centrosome/ Mitotic spindle poles Microtubule organizing center [16,36]
Spindle pole
bodies (SPB)
U bodies Sites for assembly & storage of uridine-rich snRNPs [23]
(spliceosome)
Nuclear Nucleoli Forms around actively transcribing Function in rRNA transcription, processing and [38]
bodies (singular: ribosomal gene clusters ribosomal subunit assembly
nucleolus)
Histone locus Associated with chromosomal locus Transcription and 3′-end processing of [24,25]
bodies (HLB) of histone genes replication-dependent histone genes
Cajal bodies Spheres, coiled bodies Associate transiently with specific Involved in biogenesis of histone, snRNA [13,25]
(CBs) genomic loci (spliceosome) and small nucleolar (sno)RNA genes;
function in trafficking of snRNPs and snoRNPs
PML bodies ALT-associated PML bodies, Associate transiently with specific Induced by DNA damage; to maintain telomeres using [35]
ND10-, PODs (PML oncogenic genomic loci an alternative recombination-mediated lengthening
domains) or Kr bodies mechanism
Speckles Interchromatin granule Often associated with Cajal bodies Involved in the storage, assembly and modification of [33]
cluster pre-mRNA splicing factors
Paraspeckles Interchromatin space of the Regulate gene expression by retaining RNAs in the [12]
nucleoplasm nucleus
Nuclear Nucleoplasm of human cells; frequently Form in response to heat shock; participate in rapid [9]
stress bodies adjacent to chromatin blocks changes of gene expression through chromatin
remodeling and trapping of transcription and splicing
factors
Clastosome Nucleoplasm Form when elevated levels of proteins targeted for [20]
proteasome-dependent degradation queue up for
proteolysis, recruit additional proteins for the
proteasome
Cleavage Adjacent to Cajal bodies Functions in RNA transcription, splicing, and/or [22]
bodies processing; preferentially required during DNA
replication; perhaps also for histone gene transcription
OPT (Oct1/ Appear in G1 phase next to nucleoli Sites where particular genes and [29]
PTF/ transcription factors are concentrated
transcription)
domains
Polycomb Associated with heterochromatin; Transcriptional repression complex [31]
(PcG) bodies larger foci localized near centromeres e.g. of Hox genes
L. Malinovska et al. / Biochimica et Biophysica Acta xxx (2013) xxx–xxx 3
examples. Even though these structures are morphologically very aggregation [53]. This indicates that structural changes can significantly
diverse, they can be broken down into two different functional groups: alter the phase behavior of biomolecular solutions.
active biochemical reaction centers and inactive storage compartments. The fraction of the cytoplasm that contains macromolecules is
To assemble such membrane-free compartments in the cellular remarkably high, occupying up to 30% of the available volume. In
environment, large numbers of macromolecules have to interact in this high concentration environment, crowding effects are likely to
a coordinated manner. Templates do not seem to be necessary for play important roles. This is because large parts of the cellular space
this process, as suggested by the finding that many structures form de are occupied by uninvolved macromolecules, reducing the amount
novo by using up soluble pools of macromolecules [40–42]. Strikingly, of solvent that is available to a certain macromolecular species. This
once a self-organizing structure is established, it can be maintained excluded volume effect can dramatically increase the thermodynamic
against steep concentration gradients over long timescales. With modern activity or effective concentration of macromolecules. A crowded
live cell imaging techniques, such as fluorescence recovery after photo environment can therefore alter the rates and equilibrium constants
bleaching (FRAP), we can now study the dynamics of membrane-free of biomolecular reactions, affecting enzymatic reactions and protein
compartments in living cells. The surprising finding is that the constitu- complex formation [48,54]. For large macromolecular assemblies,
ents of these compartments turn over on the order of seconds to minutes the excluded volume effect becomes a significant force and has conse-
[43–47]. They can also rapidly undergo changes in number and size. quently been proposed to drive the formation of large cellular struc-
Thus, as predicted by the theoretical model of self-organization, these tures [54,55]. Consistent with this, RNP granule assembly is strongly
structures undergo constant changes on the molecular level, while at affected by crowding reagents [56].
the same time being able to retain their identity. This, of course, raises In the presence of an excluded volume effect, phase transitions are
the question of how a structure can be preserved in the face of constant expected to occur at much lower macromolecular concentrations.
reorganization. Given the abundance of macromolecules in living cells, Walter and
The purpose of this article is to highlight the important role of Brooks suggested that phase separations should be a frequent occur-
protein disorder for biological self-organization. We propose that rence in biological liquids [57]. The large number of different macro-
self-organizing macromolecular collectives are critically dependent molecular species even makes it conceivable that multiple liquid
on intrinsic disorder to remain dynamic and mediate their cellular phases could locally coexist. In the next section, we will examine
functions. Importantly, intrinsically disordered regions within such the evidence for phase separation in living cells.
assemblies are often compositionally similar to prion proteins. Their
prion-like nature, however, makes them prone to misfold and aggre- 2.2. Phase transitions in biological systems
gate. As a consequence, many of these proteins are now emerging in
connection with protein misfolding diseases. Phase separation in biological systems remained a theoretical
Self-organizing macromolecular collectives often undergo dramatic concept for a long time; only few clear cases in living cells were
physicochemical transformations. Therefore, as a first attempt to unravel reported. Early studies suggested a role for phase transitions in
the relationship between protein disorder, prion propensities and the structuring of membranes. Mixtures of phospholipids and cho-
self-organization, we will discuss several pertinent concepts from phys- lesterol can undergo phase transitions, thus providing a possible
ics and chemistry. basis for membrane organization in living cells. Subsequent studies
indeed confirmed that biological membranes show rich phase be-
havior. Many membranes in living cells can for example form lipid
2. Phase transitions rafts, specialized membrane microdomains, which serve as orga-
nizing centers for signaling molecules [58].
2.1. The rich phase behavior of macromolecules Other examples of phase transitions were reported in association
with stressful environmental conditions [59]. Stress causes protein
Phase transitions are a common occurrence in nature. A phase transi- misfolding, and the resulting non-native proteins can clump together
tion takes place when a thermodynamic system switches from one state to form particles of very high molecular weight. Because these protein
of matter to another. Liquids, such as water, can transform into a gas aggregates have the tendency to become insoluble in aqueous solu-
upon heating to the boiling point, causing abrupt changes in their phys- tions, stress is often accompanied by liquid–solid phase separations.
ical properties. Phase separation can also occur when two or more Although protein misfolding and aggregation are barely detectable
distinct macromolecular species are dissolved in an aqueous solution. in cells under optimal conditions, they are frequently observed in
Perhaps the most commonly used and best-understood example in association with disease or aging. Aberrant phase transitions in cells
polymer chemistry is an aqueous two-phase system of two neutral of the eye lens, for example, cause cataracts, a disease in which the
polymers: polyethylene glycol and dextran. When these two polymers normally clear cytoplasm of these cells becomes opaque. To allow
are mixed, they undergo repulsive interactions that lead to the formation the passage of light, healthy eye lens cells lack larger-sized organelles
of two stable liquid phases [48,49]. More complex phase behavior is and contain a concentrated solution of crystalline proteins. Under
observed for strongly interacting polymers such as polyelectrolytes of normal physiological conditions, these proteins exist in a single trans-
opposite charge [50]. In this case, the phase separation is heavily parent phase. However, because of aging, the crystalline proteins
influenced by other factors such as the ionic strength of the solution. phase separate, forming liquid droplets and solid aggregates that pre-
Phase systems containing biological molecules have received less vent the passage of light.
attention than synthetic polymer systems, most likely because of their Do cells normally avoid phase separation as in the cytoplasm of eye
greater complexity. Despite this fact, limited thermodynamic compati- lens cells or can phase separation also be a means for spatiotemporal
bilities have also been observed for diverse biomolecules [51,52]. Be- organization? Two recent studies suggest that liquid–liquid demixing
cause biological macromolecules are more structured and compact, phase transitions could indeed be functionally important [60,61]. In
higher concentrations are generally needed to induce phase behavior. one report, the authors investigated the dynamics of P granules, RNA-
Consistent with findings from polymer science, differences in hydrophi- rich bodies in embryos of Caenorhabditis elegans [62]. Components in-
licity are the most important factors that determine whether two given corporated into P granules were in a dynamic equilibrium with a solu-
macromolecules are compatible or not. A factor that strongly affects ble pool in the cytoplasm. Remarkably, P granules showed liquid-like
the compatibility of proteins is denaturation. It can even lead to self- behavior, including fusion between P granule droplets, dripping in
incompatibilities in mixtures containing a native and a denatured form response to shear stress, and wetting of membranes. Using these mac-
of the same protein, thus triggering a phenomenon known as roscopic behaviors, the authors could determine values for viscosity
and surface tension, which were very similar to those reported for col- also important to point out that fuzzy complexes constitute indepen-
loidal polymer systems. dent functional states; they are not intermediates on the way to more
Another study by Rosen et al. showed that mixtures of multivalent compact structures. As we will see later, the maintenance of fuzziness
macromolecules could assemble into liquid droplets [63]. The authors is essential for cellular survival, because conversion of fuzzy complexes
focused on a system of three proteins: NCK, N-WASP and nephrin. In into aberrant static structures can trigger catastrophic protein misfolding
this three-component system, phase transitions were observed in the and aggregation.
presence of three different protein–protein interaction sites: SH3 do- IDPs within fuzzy complexes often interact with their binding
main repeats in NCK, proline-rich motifs in N-WASP, and phosphorylat- partners via short linear motifs (SLiMs). SLiMs are regions that consist
ed tyrosine residues in nephrin. Synthetic constructs that contained of only 2–8 amino acids [74–77]. They interact with a diverse set of
multiple repeats of these motifs readily formed liquid droplets in vitro globular motif-recognition domains, including classic protein–protein
and in vivo. Droplet formation was also observed for other multidomain interaction domains such as SH3, SH2, or WW. Upon binding to
proteins, including the RNA-binding protein PTB in association with a motif-recognition domain, SLiMs often undergo a conformational
short fragments of RNA. Thus, multiple weak interactions are sufficient change to adapt to the structure of the binding partner. Because of
to drive a multicomponent system into a phase-separated state. This is the small size of the target motifs, SLiM-mediated binding events
consistent with findings in polymer theory where the propensity to are usually weak, transient, and have low specificity [75,76]. Howev-
phase separate increases with the number of binding sites. The findings er, interactions may become stronger or more specific through coop-
from Rosen et al. suggest that large phase-transitioning protein assem- erative binding events, involving multiple SLiMs and several globular
blies need to fulfill specific structural requirements. In the following protein–protein interaction domains. This multiplicity of binding was
sections, we argue that intrinsically disordered protein regions are proposed to enable combinatorial decision-making processes and the
particularly well adapted to meet these demands. formation of macromolecular complexes [77].
Despite the extreme evolutionary agility of IDRs, a recent compar-
3. Intrinsic disorder in proteins ative study succeeded in identifying a large number of putative SLiMs
in intrinsically disordered domains [78,79]. The study was based on
3.1. Intrinsically disordered proteins: abundant and versatile the assumption that functionally relevant motifs have a higher degree
of conservation than their surrounding background regions. The find-
Proteins with regions of little or no structure, so-called intrinsically ings suggest that at least 5% of amino acids in IDRs function as SLiMs.
disordered regions, frequently occur in eukaryotic proteomes. According However, what is the function of the remaining 95%? SLiMs require
to conservative estimates, about 30% of eukaryotic proteins contain malleable sequence environments to perform their function [80].
regions of more than 30 amino acids that do not adopt a defined Therefore, the remaining sequence play important roles as adaptable
structure [64–66]. On the sequence level, IDRs are depleted in bulky carrier sequences that optimize and regulate the interaction between
hydrophobic and aromatic residues and are often enriched in polar or SLiMs and their binding partners. How sequence characteristics can
charged residues (arginine, glutamate, lysine, glutamine, and serine) or modulate the conformation of IDRs on a more global level will be
structure-breaking amino acids (glycine and proline) [67]. Consistent discussed in the next section.
with this, a typical IDP features a low overall hydrophobicity, a high
mean charge, and, in many cases, a low sequence complexity. 3.3. Solubility and phase behavior of intrinsically disordered proteins
Despite being highly flexible and lacking a defined three-dimensional
structure, intrinsically disordered proteins (IDPs) have important biolog- Many homogenous protein solutions become thermodynamically
ical functions. IDPs play critical roles in gene regulation, signaling, and unstable when the protein concentration is above a few micromoles.
intracellular transport, and are often found at central positions in protein This is due to the fact that the number of repulsive and attractive
interaction networks [67–70]. Based on their molecular functions, IDRs interactions increases linearly with protein concentration. Above a
can be grouped into four different classes: regions that (1) function as en- certain critical point, the system is driven into a thermodynamically
tropic chains; (2) are modified by posttranslational modifications; (3) are more stable, phase-separated state. This effect is even more pro-
involved in molecular recognition; (4) facilitate molecular assembly. nounced in crowded environments, in which a protein is confronted
Thus, the functional diversity of IDRs is similar in extent to that of their with a large number of additional heterotypic interactions. However,
foldable counterparts. Like compact globular proteins, IDPs also frequent- a protein's solubility is not only dependent on the concentration but
ly interact with other macromolecules. When IDPs interact with their also strongly influenced by its folding state. Early in vitro experiments
corresponding binding partners, they can undergo dramatic structural for example showed that the critical concentrations are higher for
changes. However, disorder to order transitions have only been observed pairs of globular proteins than for pairs where one of the components
for a subset of IDPs. In fact, recent studies indicate that many IDRs remain is a random coil [52]. This, and the observation that proteins readily
disordered upon complex formation, a phenomenon, which was termed form insoluble aggregates when the conditions become unfavorable,
fuzziness. suggests that proteins are only marginally soluble in biological liquids
[81]. Hence, protein folding may be viewed as a cellular strategy to
3.2. Protein complex fuzziness and short linear motifs keep a protein soluble.
Unlike globular proteins, IDPs cannot adopt a defined structure in
Many protein complexes contain significant amounts of structural the absence of their ligands. If we assume that all proteins have
disorder in the bound state, a phenomenon that has largely been evolved to remain soluble throughout the lifetime of an organism,
overlooked so far [71–73]. Four different conceptual models have than IDPs must have developed alternative mechanisms to retain
been put forward to describe the functions of disordered regions within their solubility in the crowded environment of the cell. Recent com-
such fuzzy complexes: they may (1) adopt multiple alternative confor- putational and experimental studies found that isolated IDPs often
mations (polymorphic model); (2) act as linkers that increase the con- form disordered globule states [82–87]. Importantly, these globules
formational freedom and adaptability of two interacting regions (clamp are not characterized by a defined structure but comprise an ensem-
model); (3) contain sites for binding partners or posttranslational mod- ble of conformations with similar compactness and stabilities. Stud-
ifications (flanking model); (4) remain completely disordered as part of ies on simple homopolymeric sequences such as polyglutamine or
their normal function (random model). Fuzziness is functionally impor- polyglycine have also revealed that water is a poor solvent for polar
tant in a variety of settings, because it adds adaptability, versatility, and IDPs [82,88]. The collapsed state of such homopolymers is maintained
reversibility to protein binding and complex formation [71–73]. It is through a dynamic network of internal hydrogen bonds, involving, for
the most part, backbone-to-backbone interactions. Given that many The prion properties of prion proteins reside in structurally indepen-
IDPs are compositionally and physicochemically similar to these arche- dent prion-forming domains (PrDs). These domains are highly enriched
typal IDPs, partially or fully collapsed states are likely to be a common for uncharged polar amino acids such as glutamine, asparagine, glycine,
occurrence. Consistent with this, a recent study found that the IDR of proline, serine, and tyrosine [97,108]. PrDs are at least 60 amino acids in
the translation termination factor and prion protein Sup35 adopts a length and predicted to be intrinsically disordered. A few experimental
collapsed state in aqueous solutions [84]. This suggests that these studies have explored the conformational properties of PrDs in their
principles also hold for more complex, naturally evolved domains. non-prion conformation and have indeed found that they are largely
Multidomain interactions between regulatory proteins require the disordered [84,109]. Despite their general tendency toward disorder,
simultaneous exposure of multiple SLiMs. However, if IDRs frequently they can spontaneously assemble into an amyloid-nucleating confor-
adopt a collapsed state, than these functional motifs could be hidden mation. This transition involves a collapse of disordered monomers
in the interior of the globule. To prevent this from happening, the into various pre-molten and molten oligomers [84,110–112]. Disorder-
local sequence context is tuned to optimize the accessibility of SLiMs to-order transitions of polypeptides within these oligomers are
in space and time [72,80,89]. Importantly, proline residues, which augmented by additional intermolecular interactions, eventually leading
would interfere with a conformational collapse because of their confor- to the formation of an oligomer with characteristic cross-β structure.
mational rigidity, are highly enriched in SLiM-containing IDRs [80]. This Once this structure is established, amyloid formation becomes self-
suggests that proline residues could be used to locally regulate SLiM sustaining and grows by depleting soluble conformers of the same
availability. Glycine residues could also play an important role, because protein.
they entropically prefer conformational disorder. The conformation of
IDRs is also strongly dependent on the net charge per residue, with
higher net charges promoting globule-to-coil transitions [90,91]. Long 4.2. Identifying prion-like IDRs on a genome-wide level
IDRs with complex charge distributions could even prefer extended
structural ensembles in which multiple globules are connected by The distinctive compositional features of the founding yeast prions
short flexible linkers. The preference for such elaborate geometries Sup35 and Ure2 stimulated the development of bioinformatics algo-
could be regulated by other factors such as the ionic strength or posttrans- rithms to detect prion-like proteins on a genome-wide scale. Initial
lational modifications. Thus, a rich variety of conformational possibilities attempts looked for an enrichment of asparagine and glutamine resi-
is emerging from simple design features such as the physicochemical dues in a sequence stretch of defined size [113]. These studies revealed
characteristics of side chains or enzymatically introduced covalent modi- that prion-like domains are quite common in eukaryotic proteins but
fications. Deciphering this conformational code will be one of the rare in prokaryotes. They also helped to uncover additional prion pro-
challenges that protein scientists need to tackle in the years to come. teins, such as Rnq1 in yeast [114] and CPEB in Aplysia [115]. Although
these simple approaches generated long lists of potential prion candi-
4. Prion-like intrinsically disordered proteins dates, the number of experimentally verified prions remained low.
To more reliably predict prion proteins in large proteome datasets, a
4.1. Prion-like IDRs have an intrinsic ability to assemble into amyloids refined algorithm was developed based on the inherent similarity to
known yeast prions. Using this algorithm, the yeast proteome was
IDPs are a diverse group of proteins with various functions. Here, we screened for prion-like proteins [97,116]. The algorithm returned
want to limit ourselves to a subset of such IDPs containing long about 200 candidates, which were ranked according to their composi-
intrinsically disordered domains that are highly enriched for uncharged tional similarity to experimentally confirmed prions. A subsequent
polar residues. We propose that these sequences are intimately in- experimental analysis of the first 100 candidate PrDs – the analysis
volved in the formation of fuzzy macromolecular collectives. However, was limited to the prion-like portions because of the previously demon-
they have initially gained attention for their ability to self-assemble strated transferability of PrDs – identified 19 domains with prion prop-
into one of the most highly ordered structures in biology: amyloids. erties and many additional domains that were aggregation-prone.
Amyloids form when large numbers of an amyloidogenic protein What distinguishes prion-forming domains from domains that
associate to form a fiber that is a single extended β-sheet. This cross-β do not form prions? Domains with a propensity to form prions
structure imparts special features: a high affinity for dyes such as or amyloids were enriched for asparagine and depleted for glutamine,
Thioflavin T and Congo Red and an extraordinary resistance to denatur- proline, and charged residues [97]. The prevalence of prolines and
ants [92]. The crystal-like organization of amyloids also has important charged residues in non-amyloid-forming domains is in agreement
functional implications, endowing them with the ability to self-replicate. with previous knowledge: prolines are inherently inflexible and can
Remarkably, amyloids also have transmissible properties; Fragments of interfere with the formation of secondary structure; charged residues
amyloid are passed between cells or organisms, and the self-templating are disfavored because of potentially repulsive interactions and their
ability of amyloid then replicates the structure, giving them an infectious general tendency for hydration. However, the uncovered distinction
property [93–96]. Proteins with such infectious properties are known as between asparagine and glutamine was unexpected, as these residues
prions. were considered to be equally potent in promoting prion formation
Prion mechanisms are causing several mammalian neurodegenera- [113,114,117].
tive diseases, such as Creutzfeldt–Jakob disease and mad cow disease. An extensive mutational study confirmed opposing roles for these
However, in single-celled organisms such as yeast, prions can act as epi- two chemically related amino acids [118]. Changing asparagines to
genetic elements that impart specific heritable phenotypes. Depending glutamines in prion proteins decreased prion formation and increased
on the genetic background and the environmental conditions, these the propensity to form proteotoxic, non-amyloid aggregates. In con-
phenotypes can be advantageous, benign, or detrimental [97–101]. trast, changing glutamines to asparagines enhanced prion formation
This led to the proposal that prions are adaptive bet-hedging devices and reduced toxicity. This finding could have important implications
that enable survival in stressful environments by creating selectable for distinguishing disease-causing aggregation-prone proteins from
phenotypic diversity [95,96,102,103]. However, this view is controver- functional prions. Efforts to predict prions were also undertaken by
sial and others have suggested that yeast prions are molecular degener- other groups. Ross et al. for example have developed a different method
ative diseases [104–106]. Recent evidence, however, shows that prions that ranks candidate proteins using experimentally derived prion pro-
abundantly occur in wild yeast strains, suggesting that they may very pensities [108,119]. This method was able to distinguish between
well act as evolutionary capacitors that facilitate the survival of yeast prion and non-prion domains with high accuracy and it revealed a facil-
in their natural habitats [107]. itating role for hydrophobic residues.
How conserved are the prion properties of these domains? Recent This conclusion was inspired by earlier studies focusing on a group
results from the Wickner lab suggest that domains with prion-like of related proteins, the FG repeat-containing nucleoporins [130–133].
amino acid compositions can exist over long evolutionary time scales FG nucleoporins are subunits of the nuclear pore complex, and, like
without being able to assume a prion conformation. A case in point is many RNA-binding proteins, contain intrinsically disordered prion-
the PrD of the yeast prion Ure2. Even though the Ure2 proteins of like domains with periodically occurring hydrophobic repeats. In
Saccharomyces castellii, Kluyveromyces lactis, and Candida glabrata the case of the nucleoporins, however, these repeats consist of
contain prion-like domains that are very similar to the PrD of Saccha- phenylalanines and glycines (therefore FG repeats). Interestingly,
romyces cerevisiae Ure2, these regions could not undergo a structural FG nucleoporins proteins were among the proteins that were precip-
transformation to a prion state [120–122]. Conversely, the more itated by b-isox [128,129]. Moreover, earlier studies had shown that
distantly related PrD of Candida albicans was able to form a prion isolated FG-repeat domains assemble into hydrogels [130,131]. Be-
[120]. The continued presence of these compositional biases despite cause of their sieve-like properties, the authors proposed that
any discernible prion functionality suggests that other, non-prion func- hydrogels form the molecular basis for the size-exclusion barrier at
tions are underlying their conservation. In agreement with this idea, alter- the nuclear pore. Consistent with this, Frey et al. demonstrated that
native functions have occasionally been proposed [123–125]. Together, some FG domain hydrogels allowed highly selective access of nuclear
these data suggest that the prion-like amino acid composition is pre- transport receptors but rejected other proteins of similar size [130,131].
served for other reasons, thus hinting at the possibility that the prion pro- What are the structural features required for hydrogel formation
pensities of some of these domains are an epiphenomenon. by FG domain proteins? Initial results identified a critical role for
phenylalanines [130,131,133]. However, a later report found that
the cohesiveness of phenylalanines was not sufficient to explain the
4.3. Prion-like IDRs are aggregation-prone physical properties of hydrogels [132]. Using solid-state NMR spec-
troscopy, this study was able to pinpoint an additional type of intragel
Recent studies using the above-described algorithm have uncovered interaction: intermolecular β-sheets between the asparagine-rich
a number of proteins with prion-like domains in the human proteome spacer regions. This interaction was subsequently shown to be critical
[126,127]. In agreement with findings from yeast [97], many of these for the stability of the hydrogel. Hence, it was proposed that amyloid-
proteins contained RNA-binding domains. Disconcertingly, however, like structures are the key elements that drive the formation of the
the same proteins are now emerging in connection with several neuro- size-exclusion barrier at the nuclear pore [132].
degenerative diseases [126]. This includes TDP-43, a protein that causes Interestingly, recent studies in C. elegans suggest a functional link
frontotemporal lobar degeneration and amyotrophic lateral sclerosis between the nuclear pore and P granules [134]. P granules are proto-
(ALS), and FUS, a protein mutated in certain familial forms of ALS. In typical RNA granules that have received much attention in recent
all these cases, prion-like IDRs seem to play key roles in establishing years. They are found in all animals and play important roles in
the underlying protein misfolding pathologies. However, if these do- maintaining the undifferentiated state of the germ cell lineage. In C.
mains pose a major threat to cellular homeostasis and are intimately elegans, P granules are often physically associated with the nuclear
linked to proteinopathies, why are they so well conserved? membrane. This led to the proposal that P granules are a functional
One possible scenario is that the prion-like domains have been con- extension of the nuclear pore complex [134]. Consistent with this
served to act as epigenetic switches during transcription or execute idea, several constitutive P granule components carry long FG repeat-
essential cellular functions in memory formation [95]. However, as containing domains, which are compositionally very similar to the FG
discussed above, the prion functionality is limited to only a subset of repeat domains of nucleoporins. Remarkably, multimerization of the
these proteins, urging us to find alternative explanations. A possible FG repeat domain of one of these proteins induced the formation of
solution is emerging from the finding that many prion-like domains cytoplasmic bodies that were reminiscent of P granules [134]. Together,
are aggregation-prone. In fact, almost 70% of the prion-like domains these data provide compelling evidence that prion-like domains with
identified in a recent systematic survey coalesced into microscopically periodically occurring aromatic residues could play key roles in the
visible aggregates when overexpressed in yeast cells [97]. Consistent formation of membrane-free compartments. However, whether this
with this observation, it was recently reported that the prion-like involves their assembly into amyloid-like filaments and the formation
sequences of many RNA-binding proteins form fibrillar structures with of hydrogels is currently a matter of intense debates [135,136].
amyloid-like properties [128,129]. Unexpectedly, these structures readi- The resistance to the hydrogel concept stems from the fact that
ly depolymerized in the presence of even low concentrations of denatur- hydrogels have so far only been observed under extreme conditions.
ants, suggesting that they are much less stable – and more dynamic – The formation of saturated FG-repeat hydrogels, for example, required
than regular amyloid. Hence, it was proposed that prion-like sequence very high protein concentrations and buffer conditions that were
stretches have evolved to function as generic aggregation domains. far-off from those in living cells [130–132]. In fact, under more physio-
This discovery was based on the serendipitous finding that a logical conditions, FG-repeat domains remained disordered and had
chemical – biotinylated isoxazole (b-isox) – precipitated a distinct set a tendency to undergo weak, reversible inter-repeat interactions
of RNA-binding proteins from cell lysate. Many of these proteins [137–139]. Thus, in the confined and highly dynamic environment of
contained low complexity regions with similarity to prion-like domains the nuclear pore, FG repeat domains are likely to be arranged into a
and were previously shown to localize to RNA granules. Among the network of reversibly interacting, disordered polypetide chains, and
identified proteins was the disease-associated protein FUS. Tyrosine-rich not into a rigid meshwork of amyloid-like filaments. Likewise, the forma-
repeats (G/SYG/S) within the FUS prion-like domain were identified as tion of FUS hydrogels was only observed at very low temperatures and at
key elements for the recruitment of FUS into b-isox precipitates. Further, extremely high protein concentrations [128,129]. Again these conditions
in vitro experiments showed that the isolated prion-like domain of FUS are unlikely to exist in living cells. The extraordinary stability of in vitro
could assemble into an elastic hydrogel. Ultrastructural studies revealed formed hydrogels is also difficult to reconcile with previous findings
that this hydrogel was composed of a three-dimensional meshwork about the liquid-like behavior of P granules in living cells (also see
of well-defined filaments. Interestingly, the X-ray diffraction patterns discussion by Weber and Brangwynne, [136]). Thus, it seems likely that
of these filaments showed that they contained considerable amounts of hydrogels are just an abnormal conformational manifestation of a
cross-β structure. Similar findings were reported for other RNA-binding group of proteins with extraordinary structural plasticity. A literature
proteins. This led the authors to propose amyloid-like polymerization of survey reveals the extreme structural versatility of FG nucleoporins.
prion-like domains as the underlying molecular mechanism of RNA These proteins have been reported to exist in an intrinsically disordered
granule formation. state [137], to form disordered amorphous aggregates [138], to adopt an
amyloid-like filamentous state [132], or to enter into a self-replicating In agreement with a potential role of prion-like IDRs in the formation
prion conformation [140]. The fact that FG nucleoporins can adopt such of large fuzzy complexes, prion-like domains have large sizes [97] and
a wide range of structures, suggests that they are extremely sensitive often contain short linear motifs [78]. To investigate the possibility that
to the conditions under which they are studied. prion-like IDRs are involved in the formation of macromolecular assem-
blies, we performed a computational analysis to identify functional
domains that are frequently associated with prion-like domains in yeast
4.4. A subset of prion-like proteins resembles elastomeric proteins
proteins. The domains that were most often found in combination with
prion-like sequences were the RNA-binding domains RRM and Pumilio
FG repeat-containing prion-like proteins are compositionally related
(Fig. 1). This is in agreement with previous studies in humans, which
to elastomeric proteins. These proteins assemble into fibrous structures
also reported a strong enrichment in RRM-containing proteins [126].
that undergo elastic recoil when released from mechanical tension and
However, other domains are also intimately linked to prion-like domains.
have important roles in elastic tissues [141]. Like FG nucleoporins and
For example, prion-like domains are frequently associated with ENTH and
RNA-binding proteins, many elastomeric proteins contain low com-
SH3, which play important roles in the formation of dynamic macromo-
plexity sequence stretches that are highly enriched for glycines, pro-
lecular networks during endocytosis and actin cytoskeleton formation.
lines, and hydrophobic amino acids.
To get further insight into the functional role of prion-like IDRs,
What structure do elastomeric proteins adopt in their functional
we grouped prion-like proteins from yeast according to their molecu-
state? Research of elastomeric proteins is plagued by a long history
lar function. Five different functional clusters were identified: tran-
of conflicting structural models. Studies provided evidence for a vari-
scription, DNA binding, RNA binding, RNA processing, and transport
ety of conformational states, ranging from highly disordered fuzzy
(Fig. 2). Clustering according to their association with cellular compo-
ensembles to rigid amyloid-like structures [141–146]. However, re-
nents also produced interesting results. It revealed that prion-like do-
cent solid-state NMR studies and molecular simulations provided
mains are most frequently found in proteins that are associated with
convincing evidence that elastomeric proteins such as elastin remain
the cytoskeleton, the nucleus, RNP complexes, or chromatin (Fig. 3).
largely disordered in the assembled state [141,147,148]. According to
This also involves a strong enrichment in proteins that are associated
this model, elastin is organized in random coils that are held together
with the cortical actin network, the nuclear pore, and RNA granules.
by scattered hydrophobic residues. In agreement with this, elasto-
Strikingly, all three of these cellular components were proposed to
meric proteins undergo phase transitions into liquid droplets in the
undergo liquid–liquid demixing phase transitions.
cellular environment [149]. Given their hydrophobic nature, it is not
As discussed in one of the previous sections, phase transitions are
surprising that elastomeric proteins are prone to form other struc-
dependent on multiple, weak interactions between multidomain
tures, such as amyloids. To prevent this from happening, elastomeric
proteins. Rosen et al. focused on the interaction network of the Arp2/
proteins contain high amounts of prolines and glycines. These resi-
3-regulating protein N-WASP to demonstrate that a system of
dues counteract the order-promoting tendencies of hydrophobic res-
multidomain proteins can transition into a liquid droplet state [63].
idues by keeping the backbone hydrated and conformationally
Consistent with an important role of prion-like proteins in this process,
disordered [141,150]. Given the extraordinary structural plasticity of
large portions of the yeast N-WASP homolog Las17 are composed of low
elastomeric and prion-like proteins, results from in vitro studies
complexity sequences, and one of these sequence stretches was even
need to be interpreted with caution. Even if experimental conditions
identified as prion-like (see Supplement for details). These protein
are used that are close to those in living cells, one cannot be sure
regions are highly enriched for proline-rich SLiMs, and many of them
whether the identified conformations reflect the true natural state
have already been shown to be involved in transient protein–protein
of these proteins. Therefore, whenever possible, attempts should be
interactions [153–155]. However, our data suggest that Las17 is just
made to investigate these proteins in situ.
one prion-like protein among many others involved in the formation
4.5. A role for prion-like IDRs in macromolecular assembly?
The presence of prion-like domains in large dynamic structures,

such as the nuclear pore complex or RNA granules, suggests a poten-
tial role for these domains in molecular assembly. In fact, disordered
protein regions are well known to play important roles in the
self-assembly of large biological structures such as viral capsids or
bacterial flagella [151]. To test the universality of this concept, Peter
Tompa et al. investigated the prevalence of protein disorder in pro-
tein complexes by interrogating protein–protein datasets from
high-throughput studies [152]. This systematic study revealed a
strong positive correlation between the size of a protein complex
and its overall amount of predicted disorder. The observed relation-
ship was even more pronounced for disordered regions that exceeded
a size of 30 amino acids, suggesting that long flexible regions assume
critical functions in protein complex assembly. Although the func-
tional role of IDRs in large protein complexes has not been studied
systematically, it seems to be emerging that most of these domains
remain at least partially disordered when in the bound state. Thus,
Fig. 1. Protein domains enriched in PrD-containing proteins from Saccharomyces
the concept of fuzzy protein complexes [71–73] will be essential for cerevisiae. PrD-containing proteins in the yeast proteome were predicted based on their
understanding the underlying molecular mechanisms of their forma- compositional similarity with known prion proteins (see Supplement for details). The
tion. According to this model, disordered regions may directly be algorithm identified 195 prion candidates, which were subsequently analyzed for their
involved in the binding process, perhaps in the form of short linear association with SMART domains using DAVID (see Supplement for details). Five types
of protein domains were enriched in PrDs: RNA-binding domains (RRM, Pumilio), epsin
motifs or sites that are modified by posttranslational modifications. homology membrane-interacting modules (ENTH), zinc finger-like DNA binding domains
Alternatively, they may provide the flexibility that is required to (GAL4), and protein interaction domains (SH3). Three of those were highly significant:
ensure productive interactions between proteins. RRM (p=3.5×10−8), Pumilio (p=6.7×10−4), ENTH domains (p=0.0013).
of large phase-separating assemblies that regulate the actin cytoskele- yeast (Fig. 5 and Supplemental Figs. S1–S5). Together, these findings
ton during endocytosis. suggest that prion-like domains are intimately involved in transcription,
In yeast, endocytosis of extracellular cargo proteins requires the chromatin remodeling, RNP complex formation, and cytoskeleton-
formation of actin patches that move inward through polymerization of dependent cellular processes. All these processes require the forma-
actin. The formation of these actin patches is dependent on a complex tion of dynamic assemblies, which, upon reaching a critical point,
molecular machinery [156,157]. The initial components that are recruited could demix into a distinct liquid state. Fuzziness emerges as a key
to actin patches include clathrin and multiple scaffold proteins and ingredient for such macromolecular assemblies, because it en-
clathrin adaptors: Yap1801 and Yap1802 (AP180 homologs), Ent1 and dows these dynamical processes with adaptability, versatility,
Ent2 (epsin homologs), Ede1 (Eps15R homolog), Scd5, Sla1, and Sla2. and reversibility.
These proteins recruit additional components, such as Pan1, End3, and Why are IDPs in self-organizing macromolecular collectives prion-
Las17, to form a complex network of interacting factors. Within this like? SLiMs and other functional motifs need to be embedded into a flex-
macromolecular assembly, Pan1 and Las17 are involved in recruiting ible sequence environment in order to function [80]. However, this critical
and activating the Arp2/3 complex to nucleate actin assembly. Strikingly, design feature – scattered order-promoting residues in a disordered carri-
most of these proteins carry prion-like domains (Fig. 4). er sequence – has a downside; it also makes these proteins prone to
To investigate whether this functional association is conserved, we misfold and aggregate. The order promoting regions can drive the sponta-
searched the proteomes of fruit flies and humans for proteins with neous collapse of prion-like IDPs into β-sheet-rich oligomers; the absence
prion-like amino acid compositions (see Supplement for the results of of order in the flanking regions further accelerates this conformational
the prediction). We discovered 656 proteins in fruit flies and 219 transformation. Once a nucleus is formed, the aggregation reaction is dif-
proteins in humans that contained a prion-like domain. The identi- ficult to stop, because IDPs are largely devoid of structural features that
fied proteins showed a functional enrichment that was similar to would prevent their incorporation into growing amyloid fibrils. Thus,
Fig. 2. Clustering of PrD-containing proteins from Saccharomyces cerevisiae according to their molecular function. PrD-containing yeast proteins were clustered according to their
molecular function using predefined GO terms (Gene Ontology). The analysis was performed with DAVID (see Supplement for details). All proteins with an EASE score ≤ 0.1 were
taken into account. Clusters were generated manually based on initially proposed clusters by the functional annotation tool of DAVID. We obtained 5 different clusters connected to
transcription, DNA-binding, RNA-binding, RNA-processing, and transport. Red lines demarcate GO terms with highly significant enrichment (p ≤0.005, ***) or significant enrich-
ment (p≤ 0.05, *). All other terms had a p value ≥ 0.05.
Fig. 3. Clustering of PrD-containing proteins from Saccharomyces cerevisiae according to their association with cellular components. PrD-containing yeast proteins were clustered
according to their association with cellular components using predefined GO terms (Gene Ontology). The analysis was performed with DAVID. All proteins with an EASE score≤0.1
were taken into account. Clusters were generated manually based on initially proposed clusters by the functional annotation tool of DAVID. We observed an enrichment of the
PrD-containing proteins in cytoskeletal compartments, in the nucleus (where we can distinguish accumulation between the nuclear pore and the nucleoplasm), in ribonucleoprotein
(RNP) complexes, and chromatin-containing structures. Red lines demarcate GO terms with highly significant enrichment (p≤0.005, ***) or significant enrichment (p≤0.05, *). All
other terms had a p value≥0.05.
we propose that the prion-like properties of many IDPs are a direct conse- that most prion-like domains have been conserved to assist weak,
quence of structural and functional constraints that enable these proteins dynamic interactions within fuzzy macromolecular collectives. Other
to assemble into large fuzzy collectives. functional roles, such as the ability to adopt a self-propagating prion
state, may sporadically arise because of the extraordinary evolutionary
4.6. A role for prion-like IDRs in stress-induced phase transitions? agility of these domains. Such self-propagating conformational states
may be an important source of heritable phenotypic diversity in yeast
Our analysis is pointing toward an important function for prion-like and other single-celled organisms [102,107]. In this section, we discuss
domains in the assembly of fuzzy macromolecular complexes. The the possibility that the structural plasticity of prion-like domains could
dynamic, self-organized state of these assemblies affords high structural also play an important role in facilitating protein aggregation in re-
flexibility and multivalent binding. This makes it very unlikely that sponse to stress.
amyloid-like conformational states are involved. Therefore, we predict Many organisms operate at temperatures where small changes
can have very dramatic effects on the solubility of their proteomes.
Consistent with this, stress or aging can lead to widespread protein
aggregation [158–161]. However, even mild environmental changes,
such as the removal of a carbon source, can cause protein aggregation
on a massive scale [39]. This raises an important question: are cells
generally trying to prevent protein aggregation or can aggregation
also be the desired consequence of a cellular program?
In agreement with the latter scenario, mounting evidence suggests
that cells can actively promote protein aggregation, specifically under
conditions of mild stress. A recent study identified two stress-inducible
compartments, termed IPOD (insoluble protein deposit) and JUNQ
(juxtanuclear quality control), in eukaryotic cells [37,162]. The JUNQ
contained highly mobile misfolded proteins and was proposed to pro-
vide a specialized environment for chaperone-mediated refolding or
protein degradation. The IPOD on the other hand contained misfolded
Fig. 4. Predicted PrDs in yeast proteins that are involved in endocytosis. Protein regions proteins that were largely immobile. Sequestration in the IPOD
with prion-like amino acid composition are highlighted in red. may reduce aberrant interactions between misfolded proteins and
Fig. 5. Comparative functional analysis of PrD-containing proteins from Saccharomyces cerevisiae, Drosophila melanogaster and Homo sapiens. PrD-containing protein were clustered
according to their molecular function or their association with cellular components using the GO term annotation of DAVID (EASE score ≤ 0.1). Clustering according to their asso-
ciation with cellular components returned four groups that were conserved across all three species: cytoskeleton, nucleus, RNP complex, and chromatin. Clustering based on mo-
lecular function produced three conserved groups: transcription, DNA binding, and RNA binding. Note that additional clusters were identified that were specific to only one or two
of the species. See Supplemental Figs. S2–S5 for more details on the GO terms.
essential cellular components, which led to the proposal that the IPOD Both the N-terminal and C-terminal extensions of sHSPs are highly flex-
could serve a cytoprotective function. Both, IPOD and JUNQ are asym- ible and at least partially disordered [169–172]. These regions have
metrically inherited in dividing yeast cells [163,164], suggesting that been implicated as binding sites for misfolded proteins and have also
they may also be involved in lineage-specific aging. been shown to regulate the oligomeric state of sHSPs. In fact, many
In agreement with the notion that protein aggregation can be a sHSPs exist as polydisperse oligomers that can change their size and
cellular strategy, protein misfolding and aggregation were not sufficient organization based on the exposure to stress or upon interaction with
to trigger the formation of JUNQ and IPOD under mild stress conditions. substrate proteins [169]. In agreement with this, sHSPs often coalesce
Compartment assembly also required the concerted action of molecular into large cytoplasmic structures in stressed cells [163,169,173]. These
chaperones, protein-sorting factors, and protein-sequestration fac- structures are co-aggregates of sHSPs and misfolded proteins where
tors [163,165]. Expression of this machinery was restricted to times the sHSPs intercalate into the aggregate to prevent the formation of
of acute stress through rapid changes in mRNA abundance and a terminally misfolded states. Thus, it is conceivable that the disordered
proteasomal feedback mechanism. This indicates that environmen- regions within sHSPs act as molecular spacers that keep misfolded
tally challenged cells can undergo controlled phase transitions to proteins in a state that is accessible to reactivation by ATP-dependent
promote the sequestration of misfolded proteins in specialized com- chaperones systems.
partments. Curiously, the two molecular chaperones that were im- Collectively, these findings and considerations suggest that certain
plicated in this process in yeast – Hsp42 and Sis1 – were predicted types of protein aggregates are not a simple consequence of random
to contain long prion-like domains [97]. protein misfolding events, but rather intended effects of a controlled
Molecular chaperones are a diverse group of proteins that bind to cellular program, which eventually culminates in the formation of
misfolded proteins to promote their re-folding and prevent the forma- granules for protein storage (the IPOD) or specialized reaction centers
tion of non-specific protein aggregates. Interestingly, recent studies for protein folding or degradation (the JUNQ). In fact, the dynamic
have shown that chaperones contain many regions that are predicted network of misfolded proteins, chaperones, and chaperone cofactors
to be disordered [166,167]. The specific function of most of these se- provides all the ingredients required for such phase transitions:
quence stretches, however, has so far remained undetermined. Despite high conformational plasticity and weak, multivalent interactions
this fact, several proposals have been made [166–168]. between its components. Intrinsically disordered domains are likely
A closer look at the group of small heat shock proteins (sHSPs) illu- to play key roles in this process, by functioning as polymorphic client
minates the potential functional roles of IDRs in chaperones. sHSPs, recognition sites and enabling the formation of phase-separated,
such as Hsp42, are a conserved group of chaperones that can associate fuzzy assemblies that remain accessible to reactivation. A recent
with a wide range of substrate proteins [169]. The major function of report provided further evidence for the involvement of prion-like
these promiscuous chaperones is to keep misfolded proteins from domains in controlled phase transitions. The authors of this study
undergoing non-productive and potentially toxic structural transitions. identified a region of the acetyltransferase p300 that is highly
disordered and displays similarities to prion-like domains [174]. In- Invariably, however, we lack a good understanding of the integrated
terestingly, this prion-like domain provided an interaction interface behavior of these parts. This is particularly obvious for the large
for various misfolded proteins, promoting their aggregation. group of intrinsically disordered proteins. These proteins are inti-
Controlled phase transitions are not limited to protein systems; mately linked to dynamic processes in living cells, but, despite their
other phase-separated granules, such as stress granules and P bodies, importance for biological self-organization, we have a very limited
contain large amounts of RNA [175,176]. P bodies and stress granules understanding of how they function on the molecular level. To
are found in all eukaryotes, suggesting that they perform an important study the molecular functions of these proteins, we need better mo-
cellular function. Current evidence indicates that P bodies mediate the lecular and computational tools, more powerful non-invasive single
repression and degradation of mRNAs. They contain a conserved set of molecule techniques, and methods that allow us to reconstruct the
proteins, which, in yeast, include the decapping enzymes Dcp1/Dcp2, full complexity of self-organizing biological systems in the test
the enhancer of decapping Edc3, and the exonuclease Xrn1. Stress tube. New conceptual advances may also be required to bridge the
granules on the other hand contain mRNAs stalled in translation initia- gap between the nano-world of molecules and the world of macro-
tion, together with translational silencers (Ngr1) and polyadenylation scopic objects. All of these are crucial steps that we need to take to
regulators (Pab1 and Pbp1), but no components of the mRNA decay understand how the dynamical organization of living cells emerges
pathway. Consistent with their distinct functions, stress granules and from the collective properties of interacting macromolecules. We
P bodies show differences in regulation, morphology, and their kinetics predict that this combined effort will not only change the way we
of assembly [175,177–179]. conceive of living systems, but will also give important insight into
Several recent studies have provided evidence that prion-like domains the catastrophic changes that occur when dynamic biological pro-
play crucial roles in RNP granule assembly [128,129,180–182]. How these cesses malfunction.
domains function on the molecular level, however, has so far remained
elusive. One possible scenario is that prion-like domains self-associate Acknowledgements
to form a meshwork of interacting proteins. This could indeed be the
case for prion-like IDRs with periodically occurring hydrophobic residues, We are grateful to the members of the Alberti Lab for critical com-
because of their strong cohesive properties. The rapid dynamics of RNP ments on the manuscript. We thank Holger Brandl and Ian Henry for
granule assembly [43–45,47,183], however, are difficult to reconcile expert technical assistance with the prion prediction algorithm. We
with amyloid-like modes of assembly, as previously proposed [128,129]. are indebted to the Max Planck Society for funding.
Another explanation is suggested by the finding that prion-like IDRs are
highly overrepresented in proteins that bind to nucleic acids (Fig. 2)
and often found in close proximity to RNA-binding domains [97]. This Appendix A. Supplementary data
argues against an independent role for prion-like IDRs in RNP granule
assembly but rather suggests that these domains could synergize with Supplementary data to this article can be found online at http://
RNA-binding domains to bind to RNA. In agreement with such a function, dx.doi.org/10.1016/j.bbapap.2013.01.003.
the mammalian prion protein PrP harbors a low complexity region that
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Biochimica et Biophysica Acta

Protein disorder, prion propensities, and self-organizing macromolecular collectives☆

1. Introduction of a new thermodynamic equilibrium. In dynamic self-assembly,

Name Other names Localization Function/description Reference

4.5. A role for prion-like IDRs in macromolecular assembly?

The presence of prion-like domains in large dynamic structures,

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