Mark W Hochstrasser, PhD

Eugene Higgins Professor of Molecular Biophysics and Biochemistry and Professor of Molecular, Cellular, and Developmental Biology

Research Interests

Research Organizations

Cancer Center, Yale: Signal Transduction

Diabetes Research Center

Molecular Biophysics and Biochemistry: Cell Cycle and Transcriptional Regulation | Hochstrasser Lab

Research Summary

We wish to understand at a molecular level how specific eukaryotic proteins are selected for rapid degradation even while most proteins are spared. Such turnover occurs primarily through the ubiquitin-proteasome system and is central to a variety of cell regulatory mechanisms, many of medical relevance. The proteasome is a molecular machine that fragments proteins into short peptides. More generally, we study the reversible enzymatic coupling of proteins to other proteins within cells. The prototypical example of such a protein modifier is ubiquitin, but at least a dozen such systems exist. While ubiquitin generally is used to mark its targets for destruction, the consequences of protein ligation to the various “ubiquitin-like proteins” are less understood. One such protein that we study, SUMO, is attached to many proteins and is crucial for cell-cycle progression. Much of our work is conducted in baker’s yeast, a model organism ideal for genetic and biochemical analysis.

Extensive Research Description

Our lab has as its general focus one of the fundamental regulatory systems of eukaryotic cells – the ubiquitin system. Ubiquitin and an array of related molecules (ubiquitin-like proteins or Ubls) such as SUMO are small, highly conserved proteins that are covalently attached to other intracellular proteins, resulting in various functional alterations of these targets. The ubiquitin system has only recently come under close scrutiny, and an extraordinary array of cell regulatory functions is gradually being uncovered. Moreover, many links are now being found between defects in this pathway and human disease, including many cancers, developmental abnormalities, Parkinson’s disease, Alzheimer’s disease, and certain severe forms of mental retardation.

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 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. We are currently studying a transmembrane ubiquitin ligase that resides in the nuclear envelope and endoplasmic reticulum. This ligase attaches ubiquitin to both nuclear regulatory proteins and to misfolded membrane proteins degraded at the ER (ER-associated degradation or ERAD). The proteasome is a large, cylindrical machine that fragments proteins into short peptides. Our primary current interest with the proteasome is its mechanism of assembly.

In our second major area of research, we are analyzing the function and dynamics of protein modification by other Ubls. 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 Ubls are poorly understood. The Ubl called SUMO is attached to many proteins in vivo and is crucial for cell-cycle progression. We discovered the first enzymes that can remove SUMO from other proteins, causing this protein modification to be highly dynamic. We are trying to understand the functional consequences of SUMO-protein modification, particularly in cell cycle checkpoints, and to determine the basis of specificity for the SUMO-cleaving proteases. Much of our work is conducted in the yeast Saccharomyces cerevisiae, an organism that permits both facile genetic manipulation and detailed biochemical analysis.

Selected Publications

  • Kusmierczyk, A., Kunjappu, M. J., Funakoshi, M. and Hochstrasser, M. A multimeric assembly factor controls formation of alternative 20S proteasomes. Nature Struct. Mol. Biol. 15, 237-244 (2008)
  • Ravid, T. and Hochstrasser, M. (2007). Autoregulation of an E2 enzyme by ubiquitin-chain assembly on its catalytic residue. Nat. Cell Biol. 9:422-427.
  • Deng, M. and Hochstrasser, M. (2006). Spatially regulated ubiquitin ligation by an ER/nuclear membrane ligase. Nature 443:827-831.
  • Lewis, A., Felberbaum, R. and Hochstrasser, M. A nuclear envelope protein linking nuclear pore basket assembly, SUMO protease regulation, and mRNA surveillance. J. Cell Biol. 178, 813-827 (2007)
  • Li, X., Kusmierczyk, A., Wong, P., Emili, A. and Hochstrasser, M. b-Subunit appendages promote 20S proteasome assembly by overcoming an Ump1-dependent checkpoint. EMBO J. 26, 2339-2349 (2007)

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