Chris Mathy

All Publications

• Emerging maps of allosteric regulation in cellular networks. Current opinion in structural biology Mathy, C. J., Kortemme, T. 2023; 80: 102602

  Abstract

  Allosteric regulation is classically defined as action at a distance, where a perturbation outside of a protein active site affects function. While this definition has motivated many studies of allosteric mechanisms at the level of protein structure, translating these insights to the allosteric regulation of entire cellular processes - and their crosstalk - has received less attention, despite the broad importance of allostery for cellular regulation foreseen by Jacob and Monod. Here, we revisit an evolutionary model for the widespread emergence of allosteric regulation in colocalized proteins, describe supporting evidence, and discuss emerging advances in mapping allostery in cellular networks that link precise and often allosteric perturbations at the molecular level to functional changes at the pathway and systems levels.

  View details for DOI 10.1016/j.sbi.2023.102602

  View details for PubMedID 37150039

• A complete allosteric map of a GTPase switch in its native cellular network. Cell systems Mathy, C. J., Mishra, P., Flynn, J. M., Perica, T., Mavor, D., Bolon, D. N., Kortemme, T. 2023

  Abstract

  Allosteric regulation is central to protein function in cellular networks. A fundamental open question is whether cellular regulation of allosteric proteins occurs only at a few defined positions or at many sites distributed throughout the structure. Here, we probe the regulation of GTPases-protein switches that control signaling through regulated conformational cycling-at residue-level resolution by deep mutagenesis in the native biological network. For the GTPase Gsp1/Ran, we find that 28% of the 4,315 assayed mutations show pronounced gain-of-function responses. Twenty of the sixty positions enriched for gain-of-function mutations are outside the canonical GTPase active site switch regions. Kinetic analysis shows that these distal sites are allosterically coupled to the active site. We conclude that the GTPase switch mechanism is broadly sensitive to cellular allosteric regulation. Our systematic discovery of new regulatory sites provides a functional map to interrogate and target GTPases controlling many essential biological processes.

  View details for DOI 10.1016/j.cels.2023.01.003

  View details for PubMedID 36801015

• A proposed workflow for proactive virus surveillance and prediction of variants for vaccine design. PLoS computational biology Baker, J. J., Mathy, C. J., Schaletzky, J. 2021; 17 (12): e1009624

  View details for DOI 10.1371/journal.pcbi.1009624

  View details for PubMedID 34914686

  View details for PubMedCentralID PMC8675697

• Systems-level effects of allosteric perturbations to a model molecular switch. Nature Perica, T., Mathy, C. J., Xu, J., Jang, G. Μ., Zhang, Y., Kaake, R., Ollikainen, N., Braberg, H., Swaney, D. L., Lambright, D. G., Kelly, M. J., Krogan, N. J., Kortemme, T. 2021; 599 (7883): 152-157

  Abstract

  Molecular switch proteins whose cycling between states is controlled by opposing regulators1,2 are central to biological signal transduction. As switch proteins function within highly connected interaction networks3, the fundamental question arises of how functional specificity is achieved when different processes share common regulators. Here we show that functional specificity of the small GTPase switch protein Gsp1 in Saccharomyces cerevisiae (the homologue of the human protein RAN)4 is linked to differential sensitivity of biological processes to different kinetics of the Gsp1 (RAN) switch cycle. We make 55 targeted point mutations to individual protein interaction interfaces of Gsp1 (RAN) and show through quantitative genetic5 and physical interaction mapping that Gsp1 (RAN) interface perturbations have widespread cellular consequences. Contrary to expectation, the cellular effects of the interface mutations group by their biophysical effects on kinetic parameters of the GTPase switch cycle and not by the targeted interfaces. Instead, we show that interface mutations allosterically tune the GTPase cycle kinetics. These results suggest a model in which protein partner binding, or post-translational modifications at distal sites, could act as allosteric regulators of GTPase switching. Similar mechanisms may underlie regulation by other GTPases, and other biological switches. Furthermore, our integrative platform to determine the quantitative consequences of molecular perturbations may help to explain the effects of disease mutations that target central molecular switches.

  View details for DOI 10.1038/s41586-021-03982-6

  View details for PubMedID 34646016

  View details for PubMedCentralID PMC8571063

• The Global Phosphorylation Landscape of SARS-CoV-2 Infection. Cell Bouhaddou, M., Memon, D., Meyer, B., White, K. M., Rezelj, V. V., Correa Marrero, M., Polacco, B. J., Melnyk, J. E., Ulferts, S., Kaake, R. M., Batra, J., Richards, A. L., Stevenson, E., Gordon, D. E., Rojc, A., Obernier, K., Fabius, J. M., Soucheray, M., Miorin, L., Moreno, E., Koh, C., Tran, Q. D., Hardy, A., Robinot, R., Vallet, T., Nilsson-Payant, B. E., Hernandez-Armenta, C., Dunham, A., Weigang, S., Knerr, J., Modak, M., Quintero, D., Zhou, Y., Dugourd, A., Valdeolivas, A., Patil, T., Li, Q., Hüttenhain, R., Cakir, M., Muralidharan, M., Kim, M., Jang, G., Tutuncuoglu, B., Hiatt, J., Guo, J. Z., Xu, J., Bouhaddou, S., Mathy, C. J., Gaulton, A., Manners, E. J., Félix, E., Shi, Y., Goff, M., Lim, J. K., McBride, T., O'Neal, M. C., Cai, Y., Chang, J. C., Broadhurst, D. J., Klippsten, S., De Wit, E., Leach, A. R., Kortemme, T., Shoichet, B., Ott, M., Saez-Rodriguez, J., tenOever, B. R., Mullins, R. D., Fischer, E. R., Kochs, G., Grosse, R., García-Sastre, A., Vignuzzi, M., Johnson, J. R., Shokat, K. M., Swaney, D. L., Beltrao, P., Krogan, N. J. 2020; 182 (3): 685-712.e19

  Abstract

  The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.

  View details for DOI 10.1016/j.cell.2020.06.034

  View details for PubMedID 32645325

  View details for PubMedCentralID PMC7321036

• A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature Gordon, D. E., Jang, G. M., Bouhaddou, M., Xu, J., Obernier, K., White, K. M., O'Meara, M. J., Rezelj, V. V., Guo, J. Z., Swaney, D. L., Tummino, T. A., Hüttenhain, R., Kaake, R. M., Richards, A. L., Tutuncuoglu, B., Foussard, H., Batra, J., Haas, K., Modak, M., Kim, M., Haas, P., Polacco, B. J., Braberg, H., Fabius, J. M., Eckhardt, M., Soucheray, M., Bennett, M. J., Cakir, M., McGregor, M. J., Li, Q., Meyer, B., Roesch, F., Vallet, T., Mac Kain, A., Miorin, L., Moreno, E., Naing, Z. Z., Zhou, Y., Peng, S., Shi, Y., Zhang, Z., Shen, W., Kirby, I. T., Melnyk, J. E., Chorba, J. S., Lou, K., Dai, S. A., Barrio-Hernandez, I., Memon, D., Hernandez-Armenta, C., Lyu, J., Mathy, C. J., Perica, T., Pilla, K. B., Ganesan, S. J., Saltzberg, D. J., Rakesh, R., Liu, X., Rosenthal, S. B., Calviello, L., Venkataramanan, S., Liboy-Lugo, J., Lin, Y., Huang, X. P., Liu, Y., Wankowicz, S. A., Bohn, M., Safari, M., Ugur, F. S., Koh, C., Savar, N. S., Tran, Q. D., Shengjuler, D., Fletcher, S. J., O'Neal, M. C., Cai, Y., Chang, J. C., Broadhurst, D. J., Klippsten, S., Sharp, P. P., Wenzell, N. A., Kuzuoglu-Ozturk, D., Wang, H. Y., Trenker, R., Young, J. M., Cavero, D. A., Hiatt, J., Roth, T. L., Rathore, U., Subramanian, A., Noack, J., Hubert, M., Stroud, R. M., Frankel, A. D., Rosenberg, O. S., Verba, K. A., Agard, D. A., Ott, M., Emerman, M., Jura, N., von Zastrow, M., Verdin, E., Ashworth, A., Schwartz, O., d'Enfert, C., Mukherjee, S., Jacobson, M., Malik, H. S., Fujimori, D. G., Ideker, T., Craik, C. S., Floor, S. N., Fraser, J. S., Gross, J. D., Sali, A., Roth, B. L., Ruggero, D., Taunton, J., Kortemme, T., Beltrao, P., Vignuzzi, M., García-Sastre, A., Shokat, K. M., Shoichet, B. K., Krogan, N. J. 2020; 583 (7816): 459-468

  Abstract

  A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

  View details for DOI 10.1038/s41586-020-2286-9

  View details for PubMedID 32353859

  View details for PubMedCentralID PMC7431030