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Published August 2011 | Accepted Version
Journal Article Open

The N-end rule pathway and regulation by proteolysis


The N-end rule relates the regulation of the in vivo half-life of a protein to the identity of its N-terminal residue. Degradation signals (degrons) that are targeted by the N-end rule pathway include a set called N-degrons. The main determinant of an N-degron is a destabilizing N-terminal residue of a protein. In eukaryotes, the N-end rule pathway is a part of the ubiquitin system and consists of two branches, the Ac/N-end rule and the Arg/N-end rule pathways. The Ac/N-end rule pathway targets proteins containing N^α-terminally acetylated (Nt-acetylated) residues. The Arg/N-end rule pathway recognizes unacetylated N-terminal residues and involves N-terminal arginylation. Together, these branches target for degradation a majority of cellular proteins. For example, more than 80% of human proteins are cotranslationally Nt-acetylated. Thus, most proteins harbor a specific degradation signal, termed ^(Ac)N-degron, from the moment of their birth. Specific N-end rule pathways are also present in prokaryotes and in mitochondria. Enzymes that produce N-degrons include methionine-aminopeptidases, caspases, calpains, Nt-acetylases, Nt-amidases, arginyl-transferases, and leucyl-transferases. Regulated degradation of specific proteins by the N-end rule pathway mediates a legion of physiological functions, including the sensing of heme, oxygen, and nitric oxide; selective elimination of misfolded proteins; the regulation of DNA repair, segregation, and condensation; the signaling by G proteins; the regulation of peptide import, fat metabolism, viral and bacterial infections, apoptosis, meiosis, spermatogenesis, neurogenesis, and cardiovascular development; and the functioning of adult organs, including the pancreas and the brain. Discovered 25 years ago, this pathway continues to be a fount of biological insights.

Additional Information

© 2011 The Protein Society. Published by Wiley-Blackwell. Received 11 May 2011; Revised 16 May 2011; Accepted 18 May 2011. Published online 1 June 2011. I thank T.Baker,D.Barford,C.Brower,D. Finley,M. Lynch, M. Maurizi, A. Shemorry, and B. Wadas for their helpful comments on the manuscript. I am particularly grateful to D. Finley for his detailed suggestions. I also thank D. Barford, H.K. Song, and K. Zeth for their assistance with and advice about figures.

Attached Files

Accepted Version - Varshavsky2011p14055Protein_science_a_publication_of_the_Protein_Society.pdf



Additional details

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