The Ubiquitin Pathway for the Degradation of Intracellular Proteins

Abstract

This chapter discusses the mode of action and biological functions of the ubiquitin system. Ubiquitin is a small polypeptide present in apparently all eukaryotic cells. It was originally isolated in the characterization of polypeptide hormones of the calf thymus. The sequence of ubiquitin is identical in organisms as diverse as cattle, man, toad, and insects. The extraordinary conservation of ubiquitin in evolution indicates some important cellular functions. There are two processes in which ubiquitin is known to be involved—namely, histone modification and intracellular protein breakdown. In both cases, ubiquitin is linked to protein amino groups. Though the general structure of polyubiquitin genes has been conserved in evolution, there are species differences in the number of ubiquitin repeats, number of genomic loci, and nature of the aminoacid residue(s) following the carboxyl-terminus of the last ubiquitin repeat. For direct examination of the notion that ubiquitin-protein conjugates are intermediates in protein breakdown, it is necessary to demonstrate the existence of an enzyme system that preferentially degrades proteins conjugated to ubiquitin, but not unconjugated proteins. The main enzymatic steps in the formation of ubiquitin protein conjugates have been delineated and a broad outline of the major routes of the degradation of ubiquitin-conjugated proteins has been described in the chapter. Powerful tools are now available to study the biological functions of the ubiquitin system, including specific antibodies, a temperature-sensitive mutant, microinjection techniques, and cloned genes.