Paul Schimmel, PhD
Scripps Research Joint Appointments
Other Joint Appointments
Institute for Advanced Study, Hong Kong University of Science and TechnologyScripps Florida Campus
Research Focus
Decoding Genetic Information In Translation
The genetic code was established over two billion years ago and became universally adopted by all living organisms. The rules of the code--which relate specific nucleotide triplets to specific amino acids--are established by aminoacylation reactions catalyzed by aminoacyl tRNA synthetases. In these reactions, an amino acid is associated with a specific nucleotide triplet of the genetic code, by virtue of being linked to a specific tRNA that harbors the anticodon triplet cognate to the amino acid. Because of their central role in establishing the rules of the code, the tRNAs are thought to have arisen quite early, perhaps in the context of an RNA world. The synthetases may have been amongst the earliest proteins to appear, perhaps replacing ribozymes that catalyzed the aminoacylation of primordial tRNAs. The Schimmel laboratory is interested in understanding all aspects of these systems.
Our present work focuses on the discovery of the large new biology that flows out of the tRNA synthetases. These enzymes are now known to be secreted, to have nuclear functions, and to pervade most or all parts of human biology with activities that are distinct from their catalytic function of charging tRNA. The laboratory uses methods and logic of molecular and cell biology, chemistry, and structural analysis to more deeply investigate these novel functions that have a fundamental role in maintaining organismal homeostasis, and in developing and regulating nervous, vascular, and immunological systems. The research is leading to the development of a broad new class of therapeutics to treat and cure human diseases.
Education
Ph.D., Biophysical Chemistry, Massachusetts Institute of TechnologyAwards & Professional Activities
McArthur Professor, MIT; Honors: Alfred P. Sloan Fellow; American Chemical Society Pfizer Award in Enzyme Chemistry; Elected Fellow, American Association for Advancement of Science; Elected Fellow, American Academy of Arts and Sciences; Elected Member, National Academy of Sciences, Doctor of Science (Honorary), Ohio Wesleyan University; Elected Member, American Philosophical Society; Elected member, Institute of Medicine of the National Academy of Sciences; Biophysical Society Emily M. Gray Award (co-recipient), Stein and Moore Award (The Protein Society), Chinese Biopharmaceutical Association Brilliant Achievement Award, Frank Westheimer Medal (Harvard University), Nucleic Acids Award (British Biochemical Society and Royal Society of Chemistry), David Perlman Award (American Chemical Society), Editorial Boards: Accounts of Chemical Research; Archives of Biochemistry and Biophysics; Biochemistry; Biopolymers; European Journal of Biochemistry; International Journal of Biological Macromolecules; Journal of Biological Chemistry; Proceedings of the National Academy of Sciences; Protein Science; Nucleic Acids Research; Trends in Biochemical Sciences.Selected References
For a complete list of publications: http://www.scripps.edu/schimmel/publications_schimmel.html
Guo, M. and Schimmel, P. (2013). Essential Ex-translational functions of tRNA synthetases. Nature Chem. Biol. 9: 145-153.
Zhou, H., Sun, L., Yang, X.-L., and Schimmel, P. (2013). ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase. Nature 124: 121-125.
Xu, Z., Wei, Z., Zhou, Jie J., Ye, F., Lo, C. W. S., Wang, F., Wu, J., Lau, C. C. F., Nangle, L. A., Chiang, K. P., Yang, X.-L., Zhang, M., and Schimmel, P. (2012). Internally deleted human tRNA synthetase suggests evolutionary pressure for repurposing. Structure 20: 1470-77.
Sajish, M., Zhou, Q., Kishi, S., Valdez Jr, D. M., Kapoor, M., Guo, M., Kim, S., Lee, S., Yang, X-L. and Schimmel, P. (2012). Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-gamma and p53 signaling. Nature Chem. Biol. 8: 547-554.
Guo, M. and Schimmel, P. (2011). Structural Analysis Clarifies the Complex Control of Mistranslation by tRNA Synthetases. Current Op. Struct. Biol. 22:1-8.
Guo, M., Yang, X.-L., and Schimmel, P. (2010). New functions of aminoacyl tRNA synthetases beyond translation. Nature Rev. Mol. Cell. Biol. 11: 668-674.
Guo, M., Chong, Y. E., Yang, X.-L., and Schimmel, P. (2009). The C-Ala domain brings together editing and aminoacylation functions on a single tRNA. Science 325: 744-747.
Guo, M., Chong, Y. E., Shapiro, R., Beebe, K., Yang, X.-L., and Schimmel, P. (2009). Paradox of Mistranslation of Serine for Alanine Caused by AlaRS Recognition Dilemma. Nature 462: 808-812.
Beebe, K., Mock, M., Merriman, E., and Schimmel, P. (2008). Distinct domains of tRNA synthetase recognize the same base pair. Nature 451: 90-94
Links
Team Finds Ancient Protein-Building Enzymes Have Evolved Diverse New Functions
HKUST-Scripps Scientists Discover Metamorphosed Protein-Building Enzymes as New Protein Therapeutics
Reprint: Human tRNA synthetase catalytic nulls with diverse functions
Full Text: Human tRNA synthetase catalytic nulls with diverse functions
Abstract: Human tRNA synthetase catalytic nulls with diverse functions
The Skaggs Institute for Chemical Biology
The Skaggs Institute Scientific Report
After the Genome Part 1: The Genome, We Are Sure, Is Packed with Subtleties
Simultaneous Reports by Scientists at TSRI Show How They Made Bacteria Do What Nature Doesn't