the life and death of proteins: regulation by ubiquitin and the proteasome

Mark Hochstrasser, Ph.D. Eugene Higgins Professor of Molecular Biophysics & Biochemistry Email: mark.hochstrasser@yale.edu Web site B.A., Rutgers University, 1981; Ph.D. UCSF 1987; Postdoctoral Fellow, M.I.T., 1987-1990; Assistant/Associate/Full Professor, University of Chicago, 1990-2000; Yale faculty 2000.

The research in our laboratory can be grouped into two broad and overlapping areas. First, we wish to understand, at a mechanistic and molecular level, how specific proteins are rapidly degraded within eukaryotic cells even while most proteins are spared. Such turnover is central to a great variety of regulatory mechanisms, including many of medical relevance. Much of this regulated degradation occurs via the highly conserved ubiquitin-proteasome system. The proteasome is a large, cylindrical machine that fragments proteins into short peptides. Second, we are analyzing the function and dynamics of protein modification by other proteins. The prototypical example of a protein that is covalently attached to other proteins is ubiquitin, but in recent years, evidence for at least a dozen such systems has come to light. While ubiquitin generally is used to mark its targets for destruction, the consequences of protein ligation to the various "ubiquitin-like proteins" are poorly understood. One such protein that we study, called SUMO, is attached to many proteins in vivo and is crucial for cell-cycle progression. Much of our work is conducted in the yeast Saccharomyces cerevisiae, an organism that permits both facile genetic manipulation and biochemical analysis.

Selected Publications

M. Deng and M. Hochstrasser (2006). Spatially regulated ubiquitin ligation by an ER/nuclear membrane ligase. Nature 443, 827-831.

T. Ravid and M. Hochstrasser (2007). Autoregulation of an E2 enzyme by ubiquitin-chain assembly on its catalytic residue. Nature Cell Biol. 9, 422-427.

A. Lewis*, R. Felberbaum*, and M. Hochstrasser (2007). A nuclear envelope protein linking nuclear pore basket assembly, SUMO protease regulation, and mRNA surveillance. J. Cell Biol. 178, 813-827. [*equal contribution]

A.R. Kusmierczyk, M.J. Kunjappu, M. Funakoshi, and M. Hochstrasser (2008). A multimeric assembly factor controls formation of alternative 20S proteasomes. Nature Struct. Mol. Biol. 15, 237-244.

M. Funakoshi, R.J. Tomko Jr., H. Kobayashi, and M. Hochstrasser (2009). Multiple assembly chaperones govern biogenesis of the proteasomal regulatory particle base. Cell 137, 887-899.

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