Faculty

Paul Schimmel 
Professor
Department of Molecular Biology
TSRI - 1997

Joint Appointments 
CHEMISTRY

Education 
Ph.D., Massachusetts Institute of Technology, 1966

Awards & 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; Biophysical Society Emily M. Gray Award (co-recipient), 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

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.

Selected References 
Lee, J. W., Beebe, K., Nangle, L. A., Jang, J., Longo-Guess, C. M., Cook, S. A., Davisson, M. T., Sundberg, J. P., Schimmel, P., and Ackerman, S. L. (2006). Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration in the sticky mouse. Nature 443: 50-55.

Yang, X.-L., Otero, F. J., Ewalt, K. L., Liu, J., Swairjo, M. A., Kohrer, C., RajBhandary, U. L., Skene, R. J., McRee, D. E., and Schimmel, P. (2006). Two conformations of a crystalline human tRNA synthetase�RNA complex: implications for protein synthesis. EMBO J. 25: 2919-2929.

Tamura, K. and Schimmel, P. (2006). Chiral-selective aminoacylation of an RNA minihelix: mechanistic features and chiral suppression. Proc. Natl. Acad. Sci. USA, 103: 13750-13752.

Nangle, L. and Schimmel, P. (2006). Global effects of mistranslation from an editing defect in a mammalian cell. Chemistry and Biology, 13: 1091-1100.