Class of 2004
joshsims@jhu.edu | B.S. Chemistry, University of Florida
Research
The covalent attachment of the small protein ubiquitin to targeted substrates regulates an astounding number of cellular processes. This breadth is partly attributable to the diversity in the forms of the ubiquitin signal. The ubiquitin modification can exist as covalently linked polyubiquitin chains, assembled through one of seven ubiquitin lysines. Polyubiquitin chains assembled through different lysine residues signal for distinct outcomes in the cell. This suggests that downstream interacting partners distinguish among the polyubiquitin linkages through selective binding. Indeed, several members of the largest class of ubiquitin binding domains, the ubiquitin associated (UBA) domains, have been shown to bind with selectivity for particular polyubiquitin linkages. I am trying to understand the molecular determinants of polyubiquitin selectivity by biophysically characterizing some of these UBA domains and their variants as they interact with polyubiquitin. I am also interested in the functional significance of polyubiquitin selectivities in the context of the cell. To that end, I plan to create altered-selectivity mutants of yeast UBA proteins—using both rational and combinatorial methods—with the goal of in vivo studies that will track phenotypes associated with their functions.
Publications
Sims, J.J., and R.E. Cohen. (2009) Linkage-Specific Avidity Defines the Lysine 63-linked Polyubiquitin-Binding Preference of Rap80. Mol. Cell. 33:775-83.
Schmidt, S., M.A. Pericak-Vance, S. Sawcer, L.F. Barcellos, J. Hart, J. Sims, A.M. Prokop, J. van der Walt, C. DeLoa, R.R. Lincoln, J.R. Oksenberg, A. Compston, S.L. Hauser, J.L. Haines, and S.G. Gregory. (2006) Allelic association of sequence variants in the herpes virus entry mediator-B gene (PVRL2) with the severity of multiple sclerosis. Genes Immun. 7:384–392. |
