The multicatalytic proteinase complex (MPC), also known as the 2OS proteasome, first isolated and characterized in our laboratory fifteen years ago, is a high molecular mass proteolytic molecule found in relatively high concentrations in the cytosol and nucleus of all eukaryotic cells. MPC also serves as the catalytic core of a 26S proteasome which recognizes and degrades ubiquitin-protein conjugates in an ATP-requiring reaction. The explosive growth of research on the proteasomes is accounted for by their unique structural and catalytic properties and by evidence of their essential role in several fundamental cellular processes. Ubiquitin-protein conjugates are a prominent feature in the brains of patients with neurodegenerative diseases. Exposure of a mouse neuronal cell line to a recently synthesized potent inhibitor of the """"""""chymotrypsinlike"""""""" activity of MPC leads to accumulation of ubiquitin- protein conjugates. Fundamental questions about the relationship of the structure of MPC to its function and its mechanism of action remain unanswered. Biochemical and molecular biological approaches will be employed to further characterize 2OS and 26S proteasomes in brain. The 26S proteasome will be purified and its catalytic properties defined. Ongoing studies on the expression of the heaviest MPC subunit and its role in protein degradation will be continued. Macromolecular assembly and assignment of specific catalytic functions to individual amino acid residues will be studied by molecular biological techniques. Finally more specific and potent inhibitors will be designed and synthesized. The results of these studies should provide new insights into the mechanism of action and function of a unique macromolecule which plays a significant role in CNS physiology and possibly in CNS pathophysiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029936-06
Application #
2445784
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Streicher, Eugene
Project Start
1992-07-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
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