个人简介

Tom W. Muir received his B.Sc (Hons, 1st class) in Chemistry from the University of Edinburgh in 1989 and his Ph.D. in Chemistry from the same institute in 1993 under the direction of Professor Robert Ramage. After postdoctoral studies with Stephen B.H. Kent at the Scripps Research Institute, he joined the faculty at the Rockefeller University in New York City in 1996, where he was, until recently, the Richard E. Salomon Family Professor and Director of the Pels Center of Chemistry, Biochemistry and Structural Biology. In 2011, Dr. Muir joined the Princeton Faculty as the Van Zandt Williams Jr. Class of ’65 Professor of Chemistry. In 2015, Professor Muir became the Chair of the Department of Chemistry. He has published over 150 scientific articles and has won a number of honors for his research, including; the Burrough Wellcome Fund New Investigator Award, the Pew Award in the Biomedical Sciences, the Alfred P. Sloan Research Fellow Award, the Leonidas Zervas Award from the European Peptide Society, the Irving Sigal Award from the Protein Society, the 2008 Vincent du Vigneaud Award in Peptide Chemistry, the 2008 Blavatnik Award from the New York Academy of Sciences, the 2008 Distinguished Teaching Award from The Rockefeller University, the 2012 Jeremy Knowles Award from the Royal Society of Chemistry and a 2013 Arthur C. Cope Scholar Award from the American Chemical Society. Dr. Muir is the recipient of a MERIT Award from the US National Institutes of Health and is a Fellow of American Association for the Advancement of Science and the Royal Society of Edinburgh.

研究领域

Organic Chemistry/Biochemistry and Cell Biology: Investigating the physiochemical basis of protein function in complex systems of biomedical interest with new chemical biology technologies.

Dr. Muir’s laboratory investigates the physiochemical basis of protein function in complex systems of biomedical interest. By combining tools of organic chemistry, biochemistry and cell biology, the Muir lab has developed a suite of new technologies that provide fundamental insight into how proteins work. The chemistry-driven approaches Dr. Muir has developed are now widely used by chemical biologists around the world. The Muir lab is using novel methods to study molecular recognition in prokaryotic and eukaryotic signaling processes. One of these techniques is a general approach to investigating protein activity called expressed protein ligation, which allows synthetic peptides (or other molecules) and recombinant proteins to be chemoselectively and regioselectively linked together. This is done by introducing molecular “sticky ends,” which act like Velcro, at the complementary ends of the pieces, causing them to react when mixed together in water. Introduction of these sticky ends can either be achieved chemically or biosynthetically, and it is possible to append the synthetic molecule at either end of the recombinant protein, or even insert the synthetic cassette right into the middle. This technology opens up proteins to the tools of organic chemistry by allowing researchers to incorporate unnatural amino acids, posttranslational modifications and isotopic probes into proteins at specific sites. The major focus of Dr. Muir’s current research is in the broad area of epigenetics where his group is applying in vitro protein chemistry methods to study how histone modifications control the local structure and function of chromatin. Because expressed protein ligation is an in vitro technique, the Muir laboratory simultaneously pursues complementary approaches for studying protein function in vivo. The group has developed two ways to do this, both of which exploit protein splicing, in which an intervening sequence — termed an intein — catalyzes its removal from a host protein, the extein. In trans-splicing, the intein is split into two pieces and splicing occurs only upon reconstitution of these fragments. The first of the methods is a platform technology that allows protein trans-splicing to occur only in the presence of a user specified stimulus such as a small cell-permeable molecule or red light; this “conditional protein trans-splicing” method provides a means to trigger posttranslational synthesis of a target protein from two fragments, thereby controlling that protein’s function. Conditional protein trans-splicing provides a level of temporal and spatial control over protein function that is impossible to achieve using standard genetic approaches, and Dr. Muir’s laboratory has shown that the methods works well in various cultured mammalian cell lines and in living animals. The second technique developed by the lab allows for protein semisynthesis to be performed inside living cells. Using a different type of protein trans-splicing with peptide-transduction domain technology, this method allows a targeted cellular protein to be specifically ligated to an artificial probe delivered into the cell, effectively expanding the genetic code for cell biological studies. Currently we are developing second-generation versions of this technology specifically geared towards applications in the epigenetics area. Another active area of research in the Muir lab focuses on quorum sensing in the pathogen Staphylococcus aureus. The Muir laboratory studies a class of the secreted peptides produced by the bacterium that have the ability to activate or inhibit expression of virulence, depending on which strain of S. aureus the peptides encounter. Dr. Muir and collaborators at New York University Medical Center have found that the peptides contain an unusual thiolactone structure, and further studies have suggested a mechanism that accounts for the changes in virulence. This discovery made it possible for them to design peptide analogues that globally inhibit virulence expression. These molecules are powerful tools for studying this quorum-sensing circuit both in vitro and in vivo. The Muir laboratory is currently studying the biosynthesis of these peptides and their mechanism of secretion. The group is also interested in how these peptides are recognized by their cognate cell surface receptors and how binding translates to receptor activation.

近期论文

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Eryilmaz, E., Shah, N.H., *Muir, T.W and *Cowburn, D. Structural and Dynamical Features of Inteins and Implications on Protein Splicing. J. Biol. Chem. 2014, in press Liu, Z., Frutos, S., Bick, M., Vila-Perello, M., Debelouchina, G.T., Darst, S.A. and *Muir, T.W. Structure of the Branched Intermediate in Protein Splicing. Proc. Natl. Acad. Sci. USA, 2014, in press Wang, B.; Zhao, A.; Novick, R. P.; Muir, T. W., Activation and Inhibition of the Receptor Histidine Kinase AgrC Occurs through Opposite Helical Transduction Motions. Molecular Cell 2014, 53 (6), 929-940. Shah, N. H.; Muir, T. W., Inteins: nature’s gift to protein chemists. Chemical Science 2014, 5 (2), 446-461. Wu, L.; Lee, S. Y.; Zhou, B.; Nguyen, U. T. T.; Muir, T. W.; Tan, S.; Dou, Y., ASH2L Regulates Ubiquitylation Signaling to MLL: trans-Regulation of H3 K4 Methylation in Higher Eukaryotes. Molecular Cell 2013, 49 (6), 1108-1120. Vila-Perello, M.; Liu, Z.; Shah, N. H.; Willis, J. A.; Idoyaga, J.; Muir, T. W., Streamlined Expressed Protein Ligation Using Split Inteins. Journal of the American Chemical Society 2013, 135 (1), 286-292. Tang, Z.; Chen, W.-Y.; Shimada, M.; Nguyen, U. T. T.; Kim, J.; Sun, X.-J.; Sengoku, T.; McGinty, R. K.; Fernandez, J. P.; Muir, T. W.; Roeder, R. G., SET1 and p300 Act Synergistically, through Coupled Histone Modifications, in Transcriptional Activation by p53. Cell 2013, 154 (2), 297-310. Shah, N. H.; Eryilmaz, E.; Cowburn, D.; Muir, T. W., Extein Residues Play an Intimate Role in the Rate-Limiting Step of Protein Trans-Splicing. Journal of the American Chemical Society 2013, 135 (15), 5839-5847. Shah, N. H.; Eryilmaz, E.; Cowburn, D.; Muir, T. W., Naturally Split Inteins Assemble through a “Capture and Collapse” Mechanism. Journal of the American Chemical Society 2013, 135 (49), 18673-18681. Muir, T. W., Award Address (Arthur C. Cope Scholar Awards (CSM) sponsored by Arthur C. Cope Fund). Chromatin: An expansive canvas for chemical biology. Abstracts of Papers of the American Chemical Society 2013, 246. Lewis, P. W.; Mueller, M. M.; Koletsky, M. S.; Cordero, F.; Lin, S.; Banaszynski, L. A.; Garcia, B. A.; Muir, T. W.; Becher, O. J.; Allis, C. D., Inhibition of PRC2 Activity by a Gain-of-Function H3 Mutation Found in Pediatric Glioblastoma. Science 2013, 340 (6134), 857-861. Kim, J.; Kim, J.-A.; McGinty, R. K.; Nguyen, U. T. T.; Muir, T. W.; Allis, C. D.; Roeder, R. G., The n-SET Domain of Set1 Regulates H2B Ubiquitylation-Dependent H3K4 Methylation. Molecular Cell 2013, 49 (6), 1121-1133. Kim, D.-H.; Tang, Z.; Shimada, M.; Fierz, B.; Houck-Loomis, B.; Bar-Dagen, M.; Lee, S.; Lee, S.-K.; Muir, T. W.; Roeder, R. G.; Lee, J. W., Histone H3K27 Trimethylation Inhibits H3 Binding and Function of SET1-Like H3K4 Methyltransferase Complexes. Molecular and Cellular Biology 2013, 33 (24), 4936-4946. Kee, J.-M.; Oslund, R. C.; Perlman, D. H.; Muir, T. W., A pan-specific antibody for direct detection of protein histidine phosphorylation. Nature Chemical Biology 2013, 9 (7), 416-U28. Casadio, F.; Lu, X.; Pollock, S. B.; LeRoy, G.; Garcia, B. A.; Muir, T. W.; Roeder, R. G.; Allis, C. D., H3R42me2a is a histone modification with positive transcriptional effects. Proceedings of the National Academy of Sciences of the United States of America 2013, 110 (37), 14894-14899. Barbuto, S.; Idoyaga, J.; Vila-Perello, M.; Longhi, M. P.; Breton, G.; Steinman, R. M.; Muir, T. W., Induction of innate and adaptive immunity by delivery of poly dA:dT to dendritic cells. Nature Chemical Biology 2013, 9 (4), 250-256. Vila-Perello, M.; Liu, Z.; Shah, N. H.; Willis, J. A.; Idoyaga, J.; Muir, T. W., Streamlined Expressed Protein Ligation Using Split Inteins. Journal of the American Chemical Society 2013, 135 (1), 286-292. Whitcomb, S. J.; Fierz, B.; McGinty, R. K.; Holt, M.; Ito, T.; Muir, T. W.; Allis, C. D., Histone Monoubiquitylation Position Determines Specificity and Direction of Enzymatic Cross-talk with Histone Methyltransferases Dot1L and PRC2. Journal of Biological Chemistry 2012, 287 (28), 23718-23725. Shah, N. H.; Dann, G. P.; Vila-Perello, M.; Liu, Z.; Muir, T. W., Ultrafast Protein Splicing is Common among Cyanobacterial Split Inteins: Implications for Protein Engineering. Journal of the American Chemical Society 2012, 134 (28), 11338-11341. Muir, T. W., Chromatin: An Expansive Canvas for Chemical Biology. Journal of Peptide Science 2012, 18, S20-S21.