Gregory Petsko
Weill Cornell Medicine, Neuroscience, Faculty Member
Nothing seems to engender more passion and provoke more quarrels than the matter of assigning names to things. Cell biologists seem to have about as much imagination as the American actor/screenplay writer/director Sylvester Stallone, who... more
Nothing seems to engender more passion and provoke more quarrels than the matter of assigning names to things. Cell biologists seem to have about as much imagination as the American actor/screenplay writer/director Sylvester Stallone, who came up with Rocky; Rocky II; Rocky III and Rocky IV: ... and then Rambo; Rambo II; Rambo III.
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Francis Crick once said that if you cant study function you had better study structure. He probably meant that studying function was hard but structure provided a powerful entry into the problem. But I like to think that he actually was... more
Francis Crick once said that if you cant study function you had better study structure. He probably meant that studying function was hard but structure provided a powerful entry into the problem. But I like to think that he actually was giving us his version of Once you start down that path, forever will it dominate your destiny, advice given about the danger of the Dark Side of the Force, in the movie Star Wars: The Empire Strikes Back. For if there is a dark side to the structure/function relationship, it is to be found when we search for function. We will all face the dark side before long, as the emphasis in genomics shifts from identifying and sequencing genes to the problem of determining what their products do. Leaving aside the formidable technical challenges posed by that problem, there remains the prospect that the job, as commonly considered, is impossible: because the term function means very different things to different people, and a given gene product might have ...
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My father always said one should buy the cheapest house in the best neighborhood one could afford. He reasoned that the quality of the neighborhood would ensure that the value of the property would increase with time, and the relatively... more
My father always said one should buy the cheapest house in the best neighborhood one could afford. He reasoned that the quality of the neighborhood would ensure that the value of the property would increase with time, and the relatively low price of the house would mean that it would not be over-priced and so would have a high percentage return. When I once questioned this advice on the grounds that the cheapest house might be cheap because it was poorly constructed or in need of repairs, he responded that one could always sell a relatively low-priced house to someone else if the neighborhood was good. The only thing that really matters, he said, is location. Years later I had a friend who bought and sold commercial property. He seemed to do well at it, and I asked him what his secret was. He replied with a maxim that he claimed was followed by everyone who was successful in the real-estate business. The three most important words in real estate, he said, are location, locati...
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Lessons in personal genome analysis, social networking or health information?
Research Interests: Human Genetics, Genomics, Computational Biology, Biology, Membrane Proteins, and 15 moreMedicine, Biological Sciences, Environmental Sciences, Humans, Male, Health information, Genome Analysis, Genome, Hemochromatosis, Personal Genomics, Human Genome, Single Nucleotide Polymorphism, Internet, Social Network, and European genealogy and heraldry
The retraction of 5 protein crystal structures has held back an entire sub-field for years due to the inordinately persuasive power of the pretty pictures that structural biology produces. All too often the first report is sketchy,... more
The retraction of 5 protein crystal structures has held back an entire sub-field for years due to the inordinately persuasive power of the pretty pictures that structural biology produces. All too often the first report is sketchy, superficial in its analysis, and prone to error. The second report is often more thoughtful, more useful, and is essential to the scientific process of validation and self-correction.
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We need to familiarize ourselves with the facts of evolution, so that we can mount a spirited defense against creationism and the forces of ignorance.
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In popular-culture, 'jumping the shark' refers to an abandoning of core values in an attempt to appeal to dwindling audiences, a metaphor that might be reasonably be applied to some areas of genomics-based research.
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The Nobel process for science are often somewhat controversial for who they omit. A posthumous Nobel honor could help recognize some neglected heroes.
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If we want to know for sure whether there was, or still is, life on Mars, we have to send people there.
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Repressingly, a robot scientist can generate functional genomic hypothesis and carry out experiments, increasing the working scientist's feelings of redundancy.
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Accurate criteria for death are increasingly important as it becomes more difficult for the public to distinguish between patients who are still alive from those who, through the aid of medical technology, merely look like they are alive... more
Accurate criteria for death are increasingly important as it becomes more difficult for the public to distinguish between patients who are still alive from those who, through the aid of medical technology, merely look like they are alive even though they are dead. Patients and their families need to know that a clear line can be drawn between life and death, and that patients who are alive will not be unintentionally treated as though they are dead. For the public to trust the pronouncements of medical doctors as to whether a patient is dead or alive, the criteria must be unambiguous, understandable, and infallible. It is equally important to physicians that accurate, infallible criteria define death. Physicians need to know that a clear line can be drawn between life and death so that patients who are dead are not treated as though they are alive. Such criteria enable us to terminate expensive medical care to corpses. Clear criteria for death also allow us to ethically request the ...
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A heterologously expressed form of the human Parkinson disease-associated protein α-synuclein with a 10-residue N-terminal extension is shown to form a stable tetramer in the absence of lipid bilayers or micelles. Sequential NMR... more
A heterologously expressed form of the human Parkinson disease-associated protein α-synuclein with a 10-residue N-terminal extension is shown to form a stable tetramer in the absence of lipid bilayers or micelles. Sequential NMR assignments, intramonomer nuclear Overhauser effects, and circular dichroism spectra are consistent with transient formation of α-helices in the first 100 N-terminal residues of the 140-residue α-synuclein sequence. Total phosphorus analysis indicates that phospholipids are not associated with the tetramer as isolated, and chemical cross-linking experiments confirm that the tetramer is the highest-order oligomer present at NMR sample concentrations. Image reconstruction from electron micrographs indicates that a symmetric oligomer is present, with three- or fourfold symmetry. Thermal unfolding experiments indicate that a hydrophobic core is present in the tetramer. A dynamic model for the tetramer structure is proposed, based on expected close association of...
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Research Interests: Biochemistry, Thermodynamics, Chemistry, Medicine, Macromolecular X-Ray Crystallography, and 14 moreMolecular chaperones, Humans, Endoplasmic Reticulum, Drug Delivery Systems, Enzyme, Lysosomes, Recombinant Proteins, Protein Binding, Alpha-Galactosidase, Hydrogen-Ion Concentration, Thermostability, Biochemistry and cell biology, Chemical Chaperone, and Medical biochemistry and metabolomics
Research Interests: Biochemistry, Chemistry, Crystallography, Kinetics, Medicine, and 15 moreMacromolecular X-Ray Crystallography, Crystal structure, Ligand Binding, Zinc, Methionine, Enzyme activity, Chemical Properties, Coordination number, Structure activity Relationship, Structure Function, Biochemistry and cell biology, Binding affinity, binding sites, kinetic analysis, and Medical biochemistry and metabolomics
Although much is known about the machinery that executes fundamental processes of gene expression in cells, much also remains to be learned about how that machinery works. A recent paper by O’Reilly et al. reports a major step forward in... more
Although much is known about the machinery that executes fundamental processes of gene expression in cells, much also remains to be learned about how that machinery works. A recent paper by O’Reilly et al. reports a major step forward in the direct visualization of central dogma processes at submolecular resolution inside bacterial cells frozen in a native state. The essential methodologies involved are cross-linking mass spectrometry (CLMS) and cryo-electron tomography (cryo-ET). In-cell CLMS provides in vivo protein interaction maps. Cryo-ET allows visualization of macromolecular complexes in their native environment. These methods have been integrated by O’Reilly et al. to describe a dynamic assembly in situ between a transcribing RNA polymerase (RNAP) and a translating ribosome – a complex known as the expressome – in the model bacterium Mycoplasma pneumoniae 1 . With the application of improved data processing and classification capabilities, this approach has allowed unprecede...
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Although ubiquitous in biological studies, the enhanced green and yellow fluorescent proteins (EGFP and EYFP) were not specifically optimized for neuroscience, and their underwhelming brightness and slow expression in brain tissue limits... more
Although ubiquitous in biological studies, the enhanced green and yellow fluorescent proteins (EGFP and EYFP) were not specifically optimized for neuroscience, and their underwhelming brightness and slow expression in brain tissue limits the fidelity of dendritic spine analysis and other indispensable techniques for studying neurodevelopment and plasticity. We hypothesized that EGFP’s low solubility in mammalian systems must limit the total fluorescence output of whole cells, and that improving folding efficiency could therefore translate into greater brightness of expressing neurons. By introducing rationally selected combinations of folding-enhancing mutations into GFP templates and screening for brightness and expression rate in human cells, we developed mGreenLantern, a fluorescent protein having up to sixfold greater brightness in cells than EGFP. mGreenLantern illuminates neurons in the mouse brain within 72 h, dramatically reducing lag time between viral transduction and imag...
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ABSTRACTEndosomal trafficking is a biological pathway implicated in Alzheimer’s and Parkinson’s disease, and a growing number of other neurological disorders. For this category of diseases, the endosome’s trafficking complex retromer has... more
ABSTRACTEndosomal trafficking is a biological pathway implicated in Alzheimer’s and Parkinson’s disease, and a growing number of other neurological disorders. For this category of diseases, the endosome’s trafficking complex retromer has emerged as a validated therapeutic target. Retromer’s core is a heterotrimeric complex composed of the scaffold protein VPS35 to which VPS26 and VPS29 bind. Unless it is deficient, increasing expression of VPS35 by viral vectors has a limited effect on other trimeric members and on retromer’s overall function. Here we set out to address these constraints and, based on prior insight, hypothesized that co-expressing VPS35 and VPS26 would synergistically interact and elevate retromer’s trimeric expression and function. Neurons, however, are distinct in expressing two VPS26 paralogs, VPS26a and VPS26b, and so to test the hypothesis we generated three novel AAV9 vectors harboring the VPS35, or VPS26a, or VPS26b transgene. First, we optimized their expres...
Research Interests: Biochemistry, Bioinformatics, Evolutionary Biology, Environmental Science, Developmental Biology, and 15 moreClimate Change, Computational Biology, Biotechnology, Cancer, Biology, Cell Cycle, Ecology, Drug Discovery, Evolution, Astrophysics, Functional Genomics, Astronomy, DNA, Cell Signalling, and Earth Science
Research Interests: Biology, Medicine, Macromolecular X-Ray Crystallography, Crystal structure, Software, and 15 moreHumans, Computer Simulation, Animals, Proteins, Biological evolution, Myocardium, Rabbits, Amino Acid Sequence, Nucleosides, Recombinant Proteins, Histidine, Nucleotides, Dimerization, Molecular Sequence Data, and binding sites
Mutations in DJ-1 , a human gene with homologues in organisms from all kingdoms of life, have been shown to be associated with autosomal recessive, early onset Parkinson's disease (PARK7). We report here the three-dimensional... more
Mutations in DJ-1 , a human gene with homologues in organisms from all kingdoms of life, have been shown to be associated with autosomal recessive, early onset Parkinson's disease (PARK7). We report here the three-dimensional structure of the DJ-1 protein, determined at a resolution of 1.1 Å by x-ray crystallography. The chain fold of DJ-1 resembles those of a bacterial protein, PfpI, that has been annotated as a cysteine protease, and of a domain of a bacterial catalase whose role in the activity of that enzyme is uncertain. In contrast to PfpI, a hexameric protein whose oligomeric structure is essential for its putative proteolytic activity, DJ-1 is a dimer with completely different intersubunit contacts. The proposed catalytic triad of PfpI is absent from the corresponding region of the structure of DJ-1, and biochemical assays fail to detect any protease activity for purified DJ-1. A highly conserved cysteine residue, which is catalytically essential in homologues of DJ-1, s...
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Several mutations in PTEN-induced putative kinase 1 ( PINK1 ) gene have been reported to be associated with recessive parkinsonism. The encoded protein is predicted to be a Ser/Thr protein kinase targeted to mitochondria. In this study,... more
Several mutations in PTEN-induced putative kinase 1 ( PINK1 ) gene have been reported to be associated with recessive parkinsonism. The encoded protein is predicted to be a Ser/Thr protein kinase targeted to mitochondria. In this study, we have investigated the effects of mutations on PINK1 kinase activity in vitro and on expression levels and localization in mammalian cells. We chose to examine two point mutations: G309D, which was originally reported to be stable and properly localized in cells and L347P, which is of interest because it is present at an appreciable carrier frequency in the Philippines. We were able to confirm kinase activity and produce artificial “kinase-dead” mutants that are stable but lack activity. The L347P mutation grossly destabilizes PINK1 and drastically reduces kinase activity, whereas G309D has much more modest effects on these parameters in vitro . This finding is in line with predictions based on homology modeling. We also examined the localization o...
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Research Interests: M Rna Processing, Biology, Motor neuron, Medicine, Quality Control, and 15 moreAmyotrophic Lateral Sclerosis, Biological Sciences, Saccharomyces cerevisiae, Model validation, Mutation, Genetic Screening, Neurons, Cell nucleus, Protein Domains, Protein Binding, Cytoplasm, Nucleic Acid, Gene Expression Regulation, Nonsense Mediated Decay, and Medical and Health Sciences
Loss-of-function DJ-1 mutations can cause early-onset Parkinson's disease. The function of DJ-1 is unknown, but an acidic isoform accumulates after oxidative stress, leading to the suggestion that DJ-1 is protective under these... more
Loss-of-function DJ-1 mutations can cause early-onset Parkinson's disease. The function of DJ-1 is unknown, but an acidic isoform accumulates after oxidative stress, leading to the suggestion that DJ-1 is protective under these conditions. We addressed whether this represents a posttranslational modification at cysteine residues by systematically mutating cysteine residues in human DJ-1. WT or C53A DJ-1 was readily oxidized in cultured cells, generating a pI 5.8 isoform, but an artificial C106A mutant was not. We observed a cysteine-sulfinic acid at C106 in crystalline DJ-1 but no modification of C53 or C46. Oxidation of DJ-1 was promoted by the crystallization procedure. In addition, oxidation-induced mitochondrial relocalization of DJ-1 and protection against cell death were abrogated in C106A but not C53A or C46A. We suggest that DJ-1 protects against neuronal death, and that this is signaled by acidification of the key cysteine residue, C106.
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Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The... more
Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (α-syn) aggregates in affected oligodendrocytes. Several studies point to α-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of α-syn in vitro and in neuronal cell models of α-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate α-syn pathology and to mediate neuroprotection in proteolipid protein α-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with ...
Research Interests: Chemistry, Biology, Multiple System Atrophy, Medicine, Multidisciplinary, and 14 moreTransgenic Mice, Signal Transduction, Alpha Synuclein, Humans, Mice, Animals, Substantia nigra, Neurons, Caspase, Gene Expression Regulation, Clinical Trials as Topic, Corpus striatum, proteolysis, and Protein aggregates
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The transcription factor T-bet (Tbox protein expressed in T cells) is one of the master regulators of both the innate and adaptive immune responses. It plays a central role in T-cell lineage commitment, where it controls the TH1 response,... more
The transcription factor T-bet (Tbox protein expressed in T cells) is one of the master regulators of both the innate and adaptive immune responses. It plays a central role in T-cell lineage commitment, where it controls the TH1 response, and in gene regulation in plasma B-cells and dendritic cells. T-bet is a member of the Tbox family of transcription factors; however, T-bet coordinately regulates the expression of many more genes than other Tbox proteins. A central unresolved question is how T-bet is able to simultaneously recognize distant Tbox binding sites, which may be located thousands of base pairs away. We have determined the crystal structure of the Tbox DNA binding domain (DBD) of T-bet in complex with a palindromic DNA. The structure shows a quaternary structure in which the T-bet dimer has its DNA binding regions splayed far apart, making it impossible for a single dimer to bind both sites of the DNA palindrome. In contrast to most other Tbox proteins, a single T-bet DB...