The N‐end rule pathway and regulation by proteolysis
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Open Access
- 1 June 2011
- journal article
- review article
- Published by Wiley in Protein Science
- Vol. 20 (8), 1298-1345
- https://doi.org/10.1002/pro.666
Abstract
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 Nα‐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 AcN‐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.Keywords
Funding Information
- National Institutes of Health, March of Dimes Foundation
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