Ubiquitin is a small protein of unusual conformational and evolutionary stability that participates in ATP-dependent (intracellular) proteolysis where it is conjugated to proteins prior to their degradation; this conjugation requires ATP. Ubiquitin is also found in chromatin, both in the free state and conjugated to histones. These studies aim to define further the role of ubiquitin in ATP-dependent proteolysis and to establish whether this role is related to the presence of ubiquitin in chromatin. Studies are planned: (a) to analyze ubiquitin structure in terms of factors contributing to its conformational stability and its recognition by the enzymes of ATP-dependent proteolysis; (b) to determine structure-function relationships in the enzymes that participate in ATP-dependent proteolysis; (c) to determine mechanisms involved in the selection of proteins for intracellular degradation and the role of ubiquitin conjugation in this selection and (d) to determine the relationship between the enzymes involved in ubiquitin conjugation and deconjugation during proteolysis and those involved in the analogous reactions in chromatin. Approaches to be used include studies of the effects of ubiquitin modification on its physical and biochemical properties, characterization of the binding sites for ATP and ubiquitin on the ubiquitin-conjugating enzyme, studies of protease-ubiquitin interactions, determination of the effect of protein structure on degradation in vitro by the ATP-dependent proteolysis system and study of mechanisms involved in ubiquitin conjugation in chromatin. ATP-dependent proteolysis is an essential but poorly understood process in all living cells and is a fundamental determinant of intracellular protein turnover and therefore of growth and regulation. The efficiency and selectivity of intracellular proteolysis probably plays a role in all diseases characterized by cell degeneration or atrophy, or by the synthesis of abnormal cellular proteins, as well as in the process of aging.
| Breslow, E; Chauhan, Y; Daniel, R et al. (1986) Role of methionine-1 in ubiquitin conformation and activity. Biochem Biophys Res Commun 138:437-44 |
| Breslow, E; Daniel, R; Ohba, R et al. (1986) Inhibition of ubiquitin-dependent proteolysis by non-ubiquitinatable proteins. J Biol Chem 261:6530-5 |
