Scripps Research Joint Appointments

Department of Chemistry
The Skaggs Institute for Chemical Biology
Faculty, Kellogg School of Science and Technology

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.

The cloverleaf structure of tRNA is folded into two domains--one contains the anticodon with the template reading head of the genetic code, and the other (called the minihelix domain) contains the amino acid attachment site. The minihelix domain itself is a substrate for aminoacylation, for at least ten of the synthetases. Even smaller pieces than the minihelix are active as substrates (see figure). Because these pieces lack the anticodon trinucleotides, the relationship between the sequences/structures of these active pieces (with as few as four base pairs) and the specific amino acid is distinct from the genetic code. The relationship between sequences and structures in tRNA acceptor stems and specific amino acids is referred to as an operational RNA code for amino acids. The operational RNA code is thought to have predated the genetic code.

Our recent studies have expanded upon these concepts to elucidate a role for the tRNA in amino acid fine structure recognition. That is, the ability to distinguish between two closely similar amino acids is greatly enhanced by an effector function of the tRNA, that causes the rejection of amino acids that are not exactly matched with the synthetase and its cognate tRNA. This RNA-dependent fine structure recognition may have first developed in an RNA world, and later was incorporated into the synthetase system as a critical part of maintaining the accuracy of the genetic code.

Education

Ph.D., Biophysical Chemistry, Massachusetts Institute of Technology, 1966

Awards & 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

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

The Skaggs Institute for Chemical Biology

Simultaneous Reports by Scientists at TSRI Show How They Made Bacteria Do What Nature Doesn't

The Skaggs Institute Scientific Report

After the Genome Part 1: The Genome, We Are Sure, Is Packed with Subtleties

Nature's Own Medicine for Vision Loss: Inhibitor of Angiogenesis Found by Biologists at The Scripps Research Institute