title: Three decades of studies to understand the functions of the ubiquitin family.
abstract: Many intracellular proteins are metabolically unstable or can become unstable during their lifetime in a cell. The in vivo half-lives of specific proteins range from less than a minute to many days. Among the functions of intracellular proteolysis are the elimination of misfolded or otherwise abnormal proteins; maintenance of amino acid pools in cells affected by stresses such as starvation; and generation of protein fragments that act as hormones, antigens, or other effectors. One major function of proteolytic pathways is the selective destruction of proteins whose concentrations must vary with time and alterations in the state of a cell. Short in vivo half-lives of such proteins provide a way to generate their spatial gradients and to rapidly adjust their concentration or subunit composition through changes in the rate of their degradation. The regulated (and processive) degradation of intracellular proteins is carried out largely by the ubiquitin-proteasome system (Ub system), in conjunction with autophagy-lysosome pathways. Other contributors to intracellular proteolysis include cytosolic and nuclear proteases, such as caspases, calpains, and separases. They often function as "upstream" components of the Ub system, which destroys protein fragments that had been produced by these (nonprocessive) proteases. Ub, a 76-residue protein, mediates selective proteolysis through its enzymatic conjugation to proteins that contain primary degradation signals (degrons (1)), thereby marking such proteins for degradation by the 26S proteasome, an ATP-dependent multisubunit protease. Ub conjugation involves the formation of a poly-Ub chain that is linked (in most cases) to the ε-amino group of an internal Lys residue in a substrate protein. Ub is a "secondary" degron, in that Ub is conjugated to proteins that contain primary degradation signals.
authors.affiliation: Division of Biology, California Institute of Technology, 147-75, Mail Code 156-29, 1200 E. California Blvd., Pasadena, CA 91125, USA. avarsh@caltech.edu
authors.forename: Alexander
authors.initials: A
authors.lastname: Varshavsky
mesh_terms: D009363:Neoplasm Proteins; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; C021081:recognins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease