Biochemistry and Structural biology of RNA-Protein Interactions, Translational Control of Gene Expression, and Drug Discovery

Ph.D. Johns Hopkins University
Postdoctoral: Massachusetts Institute of Technology

Our group is interested in studying RNA-protein interactions and translational control of gene expression. Specific complexes of protein and RNA carry out many essential biological functions, including RNA processing, RNA turnover, RNA folding, as well as the translation of genetic information from mRNA into protein sequences. A major research focus in my lab concerns the SmpB•SsrA quality control system for protein tagging, directed degradation, and ribosome rescue. We are also interested in understanding how sequence and structure in RNA-binding proteins contribute to the formation of RNA-protein complexes and promote specific biological functions. We use a combination of molecular genetics, protein biochemistry, functional genomics, bioinformatics, and X-ray crystallography to determine the biological function and mechanism of action of specific RNA-protein complexes. Current emphasis is on molecular characterization of how the SmpB protein recognizes SsrA RNA and promotes the detection and rescue of stalled ribosomes, in a process known as trans-translation. The relative simplicity of the SmpB-SsrA interaction, the stability of the complex, and recruitment of additional novel factors during trans-translation makes this an ideal system to study the basic principles underlying the assembly of RNA-protein complexes.

Insights gained from these investigations should further illuminate the scope of a fundamental process of life, translation. More significantly, a thorough understanding of this unique bacterial system, essential for survival of many pathogenic bacteria, should pave the way for the development of novel knowledge-based anti-infective agents that exclusively target pathogenic microorganisms. Ultimately, these insights should have implications for a better understanding of a variety of cellular processes, including the replication of RNA viruses, such as HIV, control of gene expression, and the synthesis and degradation of proteins.

Selected Publications (2005 - 2007)

[1]        T.R. Sundermeier and A.W. Karzai, Functional SmpB-Ribosome Interactions Require tmRNA, J Biol Chem 282 (2007) 34779-34786.

[2]        D. Dulebohn, J. Choy, T. Sundermeier, N. Okan and A.W. Karzai, Trans-Translation: The tmRNA-Mediated Surveillance Mechanism for Ribosome Rescue, Directed Protein Degradation, and Nonstop mRNA Decay, Biochemistry 46 (2007) 4681-4693.

[3]        J.S. Choy, L.L. Aung and A.W. Karzai, Lon Protease Degrades Transfer-Messenger RNA-Tagged Proteins, J Bacteriol 189 (2007) 6564-6571.

[4]        J. Richards, P. Mehta and A.W. Karzai, RNase R degrades non-stop mRNAs selectively in an SmpB-tmRNA-dependent manner, Mol Microbiol 62 (2006) 1700-1712.

[5]        N.A. Okan, J.B. Bliska and A.W. Karzai, A Role for the SmpB-SsrA system in Yersinia pseudotuberculosis pathogenesis, PLoS Pathog 2 (2006) e6; 50-62.

[6]        P. Mehta, J. Richards and A.W. Karzai, tmRNA determinants required for facilitating nonstop mRNA decay, RNA 12 (2006) 2187-2198.

[7]        D.P. Dulebohn, H.J. Cho and A.W. Karzai, Role of conserved surface amino acids in binding of SmpB protein to SsrA RNA, J Biol Chem 281 (2006) 28536-28545.

[8]        T.R. Sundermeier, D.P. Dulebohn, H.J. Cho and A.W. Karzai, A previously uncharacterized role for small protein B (SmpB) in transfer messenger RNA-mediated trans-translation, Proc Natl Acad Sci USA 102 (2005) 2316-2321.