Susan  A Martinis

martinis@illinois.edu

401A Roger Adams Lab
Office: (217) 244-2405
Lab: (217) 333-4936
Fax: (217) 244-5858

Mail to: Department of Biochemistry
University of Illinois
600 S Mathews Ave, M/C 712
Urbana, IL 61801
Lab Page
Video Interview

Susan A Martinis

Stephen G. Sligar Endowed Professor

Professor and Head, Departments of Biochemistry and Medical Biochemistry

Professor, Center for Biophysics and Computational Biology

Affiliate, Department of Chemistry

Research Topics

Enzymology, Molecular Evolution, Protein-Nucleic Acid Interactions, RNA Biology

Education

B.S. 1985 Washington State University
Ph.D. 1990 University of Illinois, Urbana-Champaign
Postdoc. 1990 Massachusetts Institute of Technology

RNA structure and function, RNA-protein interactions,| chemical mechanisms of biological reactions, protein synthesis, tRNA synthetases

The fidelity of protein synthesis is dependent on accurate substrate recognition by an essential family of enzymes called the tRNA synthetases. There are typically up to twenty different types of tRNA synthetases in the cytoplasm of each cell. Each is responsible for a single cognate amino acid and covalently attaches it to the correct tRNA. The "charged" tRNA then acts as a shuttle to deliver the amino acid to the ribosome where it can be incorporated into the growing polypeptide chain. Because the tRNA synthetases are essential to every cell, their investigation has potential to address basic research questions and also target important long-term medical issues such as antibiotic discovery and development. New tRNA synthetases can also be designed to incorporate novel amino acids into custom-designed proteins for use as tools and/or therapeutics in biotechnology and medical applications. Our research in tRNA synthetases currently focuses in two broad areas:

Fidelity of Protein Synthesis. Some tRNA synthetases make mistakes and fail to distinguish between closely related amino acids. However, these tRNA synthetases have evolved mechanisms to proofread their errors and edit their mistakes. One of our research goals is to determine mechanistic details and molecular interactions that govern tRNA synthetase aminoacylation and amino acid editing activities. We have made considerable progress in this area using leucyl-tRNA synthetase (LeuRS) as a model. The LeuRS editing active site resides within a discretely folded domain that is called CP1 and is distinct from the aminoacylation active site. Using combinations of biochemical, structural, computational and genetic approaches, we have localized and begun to map the amino acid editing active site and also the aminoacylation active site. Our research has identified molecular determinants that dictate specificity and also influence LeuRS enzymatic activity. Significantly, we have also been able to block the amino acid editing activity, which allows us to activate and stably charge unnatural amino acids to tRNA. These "mischarged" tRNAs can be used to expand the genetic code by introducing novel amino acids into proteins.

Novel Activities of tRNA Synthetases. The tRNA synthetases are thought to be one of the most ancient families of proteins. Because of their lengthy evolutionary period, they have often been adopted for other activities in the cell that extend beyond their role in aminoacylation and protein synthesis. A second focus of our research group is to understand the molecular basis of tRNA synthetases in alternate and novel roles that are also essential to the cell. In particular, we have focused upon a yeast mitochondrial group I intron splicing reaction that requires LeuRS. The LeuRS works in collaboration with a second protein called the bI4 maturase to aid the bI4 intron splicing reaction. We have determined that the CP1 editing domain of LeuRS can also function as an independent splicing factor and possibly suggests that some determinants for amino acid editing and splicing might overlap. We are currently investigating and characterizing specific regions and also amino acids that influence the LeuRS-dependent splicing reaction.

Representative Publications

Boniecki, M.T. and Martinis, S.A. (2012) Coordination of tRNA synthetase active sites for chemical fidelity. J. Biol. Chem., 287, 11285-11289.

Sarkar, J., Poruri, K., Boniecki, M.T., McTavish, K.K., and Martinis, S.A. (2012) The yeast mitochondrial leucyl-tRNA synthetase CP1 domain has functionally diverged to accommodate RNA splicing at the expense of hydrolytic editing. J. Biol. Chem., 287, 14772-81.

Palencia, A., Crepin, T., Vu, M.T., Lincecum Jr., T.L., Martinis, S.A., and Cusack, S. (2012) Structural dynamics of the aminoacylation and proofreading functional cycle of bacterial leucyl-tRNA synthetase., Nat. Struct. Mol. Biol, 1, doi:10.1038/nsmb.2317

Li, L., Boniecki, M.T., Jaffe, J.D., Imai, B.S., Yau, P.M., Luthey-Schulten, Z., and Martinis, S.A. (2011) Naturally occurring aminoacyl-tRNA synthetases editing domain mutations that cause mistranslation in Mycoplasma parasites. Proc. Natl. Acad. Sci., USA, 108, 9378-9383.

Sarkar, J., Mao, W., Lincecum, T.L. Jr., Alley, M.R.K., and Martinis, S.A. (2011) Characterization of Benzoxaborole-based Antifungal Resistance Mutations Demonstrates that Editing Depends on Electrostatic Stabilization of the Leucyl-tRNA Synthetase Editing Cap. FEBS Letts., 585, 2986-91.

Sarkar, J. and Martinis, S.A. (2011) Amino Acid-Dependent Shift in tRNA Synthetase Editing Mechanisms. J. Am. Chem. Soc., 133, 18510-3.

Nawaz, M.H. and Martinis, S.A. (2009) Chemistry of Aminoacyl-tRNA Synthetases. in Wiley Encyclopedia of Chemical Biology, Vol. 1 (Begley, T.P., Ed.), John Wiley & Sons, Hoboken, pp. 52- 63.

Hellmann, R. A. and Martinis, S.A. (2009) Defects in Transient tRNA Translocation Bypass tRNA Synthetase Quality Control Mechanisms. J. Biol. Chem., 284: 11478-84.

Boniecki, M.T., Tukalo, M., Hsu, J.L., Romero, E.P., and Martinis, S.A. (2009) Leucyl-tRNA Synthetase-Dependent and Independent Activation of the bI4 Group I Intron. J. Biol. Chem., 284, 26243- 50.

Pang,Y.L.J. and Martinis, S.A. (2009) A Paradigm Shift for the Amino Acid Editing Mechanism of Human Cytoplasmic Leucyl-tRNA Synthetase. Biochemistry, 48, 8958-64. (highlighted on Biochemistry’s home page).

Mascarenhas, A.P. and Martinis, S.A. (2009) A Glycine Hinge for tRNA-dependent Translocation of Editing Substrates to Prevent Errors by Leucyl-tRNA Synthetase. FEBS Letts., 583, 3443-7.

Martinis, S.A. and Boniecki, M.T. (2009) The Balance Between Pre- and Post-Transfer Editing. FEBS Letts., 584, 455-9.

Mascarenhas, A.P., Martinis, S.A., An, S., Rosen, A.E., Musier-Forsyth, K. (2008) Fidelity Mechanisms of the Aminoacyl-tRNA Synthetases, in Protein Engineering (RajBhandary, U.L. and Koehrer, C., Eds.) Springer Verlag, 153-200.

Boniecki, M.T., Vu, M.T., Betha, A.K., and Martinis, S.A. (2008) CP1-Dependent Partitioning of Preand Post-transfer Editing in Leucyl-tRNA Synthetase. Proc. Natl. Acad. Sci. U.S.A., 105,19223-8.

Complete Publications List