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Published October 10, 1986 | public
Journal Article

In vivo half-life of a protein is a function of its amino-terminal residue


When a chimeric gene encoding a ubiquitin-beta-galactosidase fusion protein is expressed in the yeast Saccharomyces cerevisiae, ubiquitin is cleaved off the nascent fusion protein, yielding a deubiquitinated beta-galactosidase (beta gal). With one exception, this cleavage takes place regardless of the nature of the amino acid residue of beta gal at the ubiquitin-beta gal junction, thereby making it possible to expose different residues at the amino-termini of the otherwise identical beta gal proteins. The beta gal proteins thus designed have strikingly different half-lives in vivo, from more than 20 hours to less than 3 minutes, depending on the nature of the amino acid at the amino-terminus of beta gal. The set of individual amino acids can thus be ordered with respect to the half-lives that they confer on beta gal when present at its amino-terminus (the "N-end rule"). The currently known amino-terminal residues in long-lived, noncompartmentalized intracellular proteins from both prokaryotes and eukaryotes belong exclusively to the stabilizing class as predicted by the N-end rule. The function of the previously described posttranslational addition of single amino acids to protein amino-termini may also be accounted for by the N-end rule. Thus the recognition of an amino-terminal residue in a protein may mediate both the metabolic stability of the protein and the potential for regulation of its stability.

Additional Information

© 1986 American Association for the Advancement of Science. 23 July 1986; accepted 8 September 1986. We thank Susan Gottesman for communicating her unpublished data, Thomas Mason and Richard Hynes for the antibody to βgal, William Lane for protein sequencing, Howard Green, Mark Solomon, John McGrath, and Stefan Jentsch for comments on the manuscript, and Barbara Doran for secretarial assistance. Supported by a grant to A.V. from the National Institute of General Medical Sciences (GM31530). A.B. is supported by an EMBO postdoctoral fellowship.

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October 23, 2023