The N-end Rule

Abstract

The N-end rule relates the in vivo half-life1 of a protein to the identity of its N-terminal residue (Varshavsky 1992). Similar but distinct versions of the N-end rule have been shown to operate in all organisms examined, from mammals to fungi and bacteria. I summarize the current understanding of the N-end rule pathway and describe some of the recent methods that utilize the N-end rule. Features of a protein that confer metabolic instability are called degradation signals, or degrons (Varshavsky 1991). The essential component of one degron, the first to be identified, is a destabilizing N-terminal residue of a protein (Bachmair et al. 1986). This signal is called the N-degron. The N-end rule (defined above) results from the existence of N-degrons containing different destabilizing residues (Varshavsky 1992). In eukaryotes, the N-degron comprises two determinants: a destabilizing N-terminal residue and an internal lysine (or lysines) of a substrate. The lysine residue is the site of formation of a multiubiquitin chain, which is required for the degradation of at least some N-end rule substrates (Bachmair and Varshavsky 1989; Hill et al. 1993; Dohmen et al. 1994). Ubiquitin (Ub) is a 76-residue protein whose covalent conjugation to other proteins (often in the form of a multi-Ub chain) plays a role in a number of processes, primarily through routes that involve protein degradation (for review, see Finley and Chau 1991; Gottesman and Maurizi 1992; Hershko and Ciechanover 1992; Jentsch 1992; Varshavsky 1992, 1995a; Parsell and Lindquist 1993; Vierstra 1993; Ciechanover 1994; Gonda 1994; Hochstrasser 1995).