Protein Structure

Protein Structure & Function
Overview of Protein Structure Hierarchy
The four levels of

protein structure are
illustrated.
Experiments have
shown that the final
3D tertiary structure
of a protein ultimately
is determined by the
primary structure
(amino acid sequence).
The 3D fold (shape) of
the protein determines
its function.
Codon Usage
Primary Structure
• The primary structure of a protein
refers to its amino acid sequence.
Amino acids in peptides (<30 aas) and
proteins (typically 200 to 1,000 aas)
are joined together by peptide bonds
(amide bonds) between the carboxyl
and amino groups of adjacent amino
acids.
• The backbone of all proteins consists

of a [-N-C(R)-C(O)-] repetitive unit.
Only the R-group side-chains vary. By
convention, protein sequences are
written from left-to-right, from the
protein’s N- to C-terminus.
•The average yeast protein contains

466 amino acids. Because the average
molecular weight of an amino acid is N
113 daltons (Da), the average CR)
molecular weight of a yeast protein is
52,728 Da. Note that 1 Da = 1 a.m.u.
(1 proton mass).
Secondary Structure:  Helix
• Secondary structure refers to short-
range, periodic folding elements that are
common in proteins.
• These include the  helix, the  sheet,
and turns.
• In the  helix, the backbone adopts a
cylindrical spiral structure in which there
are 3.6 aas per turn.
•The R-groups point out from the helix, and
mediate contacts to other structural
elements in the folded protein.
•The  helix is stabilized by H-bonds
between backbone carbonyl oxygen and
amide nitrogen atoms that are oriented
parallel to the helix axis. H-bonds occur
between residues located in the n and n + 4
positions relative to one another.
Secondary Structure:  Sheets & Turns
• In  sheets (a.k.a. “pleated sheets”),
each  strand adopts an extended
conformation.
• ß strands tend to occur in pairs or
multiple copies in  sheets that interact
with one another via H-bonds directed
perpendicular to the axis of each
strand.
• Carbonyl oxygens and amide nitrogens
in the strands form the H-bonds.
Strands can orient antiparallel or
parallel (not shown) to one another in 
sheets.
• R-groups of every other amino acid
point up or down relative to the sheet.
Most ß strands in proteins are 5 to 8
aas long. ß Turns consist of 3-4 amino
acids that form tight bends.
• Glycine and proline are common in
turns. Longer connecting segments
between ß strands are called loops.
ß turn
Tertiary Structure
•Tertiary structure refers to the folded
3D structure of a protein. It is also
known as the native structure or active
conformation.
•Tertiary structure mostly is stabilized
by noncovalent interactions between
secondary structure elements and other
internal sequence regions that cannot be
classified as a particular type of
secondary structure.
•The folding of proteins is thought to be
driven by the need to place the most
hydrophobic regions in the interior out
of contact with water.
•The structures of hundreds of proteins
have been determined by techniques such
as x-ray crystallography and NMR.
Keep in mind that most proteins are somewhat flexible and

undergo subtle conformational changes while carrying out their
functions.
Secondary Structure Motifs
Secondary structure motifs are evolutionarily conserved
collections of secondary structure elements which have a defined
conformation. They also have a consensus sequence because the
aa sequence ultimately determines structure. A given motif can
occur in a number of proteins where it carries out the same or
similar functions. Some well known examples such as the coiled-
coil, EF hand/helix-loop-helix, and zinc-finger motifs. These
motifs typically mediate protein-protein association,
calcium/DNA binding, and DNA or RNA binding, respectively.
Quaternary Structure
•Multisubunit (multimeric)
proteins have another level of
structural organization known
as quaternary structure.
•Quaternary structure refers

to the number of subunits,
their relative positions, and
contacts between the
individual monomers in a
multimeric protein.
•The quaternary structure of

the trimeric hemagglutinin
surface protein of influenza
virus is shown in the Figure.
Modular Domain Structure of Proteins
Domains are independently folding and functionally specialized
tertiary structure units within a protein.
Domains still perform their standard functions although fused

together in a longer polypeptide (e.g., DNA binding and ATPase
domains of a transcription factor).
Epidermal growth
factor (EGF) domain
Supramolecular Structure
• In many cases, multimeric proteins
achieve extremely large sizes, e.g.,
10s-100s of subunits.
• Such complexes exhibit the highest
level of structural organization known
as supramolecular structure.
• Examples include mRNA transcription
preinitiation complexes (Fig. 3.12),
ribosomes, proteasomes, and
spliceosomes.
• Typically, supramolecular complexes
function as ”macromolecular machines"
in reference to the fact that the
activities of individual subunits are
coordinated in the performance of
some overall task (e.g., protein
synthesis by the ribosome).
Evolution of Protein Families
Through genome sequencing
and classical gene cloning
approaches, the sequences
of an enormous number of
proteins have been compiled.
Comparison of sequences
shows that most proteins
belong to larger families
that have evolved over time
from a common ancestor
protein, as illustrated for
the globin family of O2
binding proteins (Fig. 3.13).
Proteins that have a common
ancestor are called
homologs. The members of a
protein family often show
>30% sequence ID, have a
common 3D fold, and usually
perform closely related
functions.
Structure of the Globin Proteins
These globular proteins are composed of mostly  helical
secondary structure. The similar folds of the globins can be
readily seen by comparing the structures of the  chain of
hemoglobin, myoglobin, and leghemoglobin (Fig. 3.13). The closely
similar structures of mammalian myoglobin and the hemoglobin 
subunit might be expected, but the resemblance of the distantly
related plant leghemoglobin is
striking. Comparison of the
sequences of the members of
protein families has brought
to light the fact that amino
acids within a given class
exhibit a large degree of
functional redundancy. In
this regard, the 3 proteins
discussed here exhibit less
than 20% identity in their
sequences, yet have the
same structure. Lastly, in
hemoglobin 2 different globin
chains have combined to form
a multisubunit protein.
Overview of Protein Folding
• Many experiments have shown that
proteins can spontaneously fold from an
unfolded state to their folded native state.
• This proves that the amino acid sequence
contains enough information to specify
tertiary structure.
• Bonds within the peptide backbone seek
out different possible conformations as the
final tertiary structure is achieved. Folding
tends to occur via successive conformational
changes leading to secondary and then
tertiary structure elements.
• The native conformation of a protein
typically is its lowest free energy, and
therefore, most stable structure.
• The unfolded (denatured) conformation of
a protein can be generated by heating or
treatment with certain organic solvents.
Chaperone-assisted Protein Folding
The folding of many proteins, particularly large ones, is
kinetically slow and is assisted in vivo by folding agents known as
chaperones. These proteins are found in all organisms and even in
different organelles of eukaryotic cells. Chaperones assist in 1)
folding of nascent polypeptides made by translation, and 2) re-
folding of proteins denatured by environmental damage, such as
heat shock. Molecular chaperones bind to unfolded nascent
polypeptide chains as they
emerge from the ribosome,
and prevent aggregation,
misfolding, and degradation.
The hydrolysis of ATP by
the chaperone drives
conformational changes that
prevent aggregation and
help drive protein folding.
Accessory proteins
participate in the process.
Eukaryotic molecular
chaperones such as Hsp 70
(cytosol & mito matrix) and
BiP (ER) are related to the
bacterial protein DnaK.
Chaperonins
Eukaryotic chaperonins such as the TriC complex are large
multimeric complexes related to the bacterial GroEL and GroES
proteins. These complexes take up unfolded proteins into an
internal chamber for folding. ATP hydrolysis drives folding.

Protein Structure

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Protein Structure

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Protein Structure & Function

Overview of Protein Structure Hierarchy

The four levels of

• The backbone of all proteins consists

•The average yeast protein contains

Keep in mind that most proteins are somewhat flexible and

•Quaternary structure refers

•The quaternary structure of

Domains still perform their standard functions although fused

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