Heads of Laboratories
Richard E. Salomon Family Professor
Selma and Lawrence Ruben Laboratory of Synthetic Protein Chemistry
muirt@rockefeller.edu
Dr. Muir’s laboratory investigates the physicochemical 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 will have widespread applications for studying protein function in the postgenomic era.
The Muir lab is using novel techniques to study molecular recognition in prokaryotic and eukaryotic signal transduction. One of these techniques is a general approach to investigating protein activity called expressed protein ligation, which allows synthetic peptides and recombinant proteins to be chemoselectively linked together. This is done by introducing bits of 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 specific protein sites. In collaboration with other Rockefeller labs, Dr. Muir is currently using expressed protein ligation to study how histone modifications control the local structure and activity of chromatin and potassium channel selectivity.
Because expressed protein ligation is an in vitro technique, Dr. Muir has been looking at different, chemistry-driven approaches for studying protein function in vivo. The lab 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 transsplicing, the intein is split into two pieces and splicing occurs only upon reconstitution of these fragments.
The first of the techniques is a system that allows protein transsplicing to occur only in the presence of a small cell-permeable molecule; this “conditional protein transsplicing” method provides a means to trigger posttranslational synthesis of a target protein from two fragments, thereby controlling that protein’s function. Conditional protein transsplicing provides a level of temporal control over protein function that’s difficult to achieve using standard genetic approaches, and Dr. Muir has shown that it works well in various cultured mammalian cell lines and in animals. Moreover, the Muir lab recently developed a version that can be controlled with light rather than with a small molecule. This technology has the potential to control protein function both temporally and spatially.
The second technique the lab developed is for protein semisynthesis inside living cells. Using a different type of protein transsplicing 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.
Another area of research in the Muir lab focuses on quorum sensing in Staphylococcus aureus. Dr. Muir is studying a class of the bacterium’s secreted peptides that has 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 inhibit only virulence expression. These molecules are powerful tools for studying this quorum-sensing circuit both in vitro and in vivo; both molecules continue to be studied by the Muir lab and could potentially be used as compounds for the development of novel therapeutics.
CAREER
Dr. Muir received his B.S. in chemistry in 1989 and his Ph.D. in organic chemistry in 1993, both from the University of Edinburgh. After studying bioorganic chemistry as a postdoc and then as a senior research associate at The Scripps Research Institute, he joined Rockefeller in 1996 as assistant professor. He was named associate professor in 2000, professor in 2002 and Richard E. Salomon Family Professor in 2005. He is also director of the Pels Family Center for Biochemistry and Structural Biology at Rockefeller.
Dr. Muir received the Blavatnik Award for Young Scientists and the Vincent du Vigneaud Award in 2008, the Irving Sigal Young
Investigator Award in 2005, the Leonidas-Zervas Award in 2002 and a Burroughs Wellcome Fund New Investigator Award in
1999. He was deemed an Alfred P. Sloan Research Fellow in 1999 and a Pew Scholar in the Biomedical Sciences in 1997. Dr. Muir
is a fellow of the American Association for the Advancement of Science.
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