The N-end rule pathway: Emerging functions and molecular principles of substrate recognition

Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Nature Reviews Molecular Cell Biology (Impact Factor: 36.46). 11/2011; 12(11):735-47. DOI: 10.1038/nrm3217
Source: PubMed

ABSTRACT The N-end rule defines the protein-destabilizing activity of a given amino-terminal residue and its post-translational modification. Since its discovery 25 years ago, the pathway involved in the N-end rule has been thought to target only a limited set of specific substrates of the ubiquitin-proteasome system. Recent studies have provided insights into the components, substrates, functions and structural basis of substrate recognition. The N-end rule pathway is now emerging as a major cellular proteolytic system, in which the majority of proteins are born with or acquire specific N-terminal degradation determinants through protein-specific or global post-translational modifications.

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    • "This pathway is highly conserved in eukaryotes and plays a key role in the regulation of many growth and developmental processes, including apoptosis, cardiovascular development, DNA replication, and response to abiotic stresses (Sriram et al., 2011). There are two characterized branches of the N-end rule pathway: the Ac/N-end rule pathway, which targets proteins with N-terminally acetylated (Ac) residues, and the Arg/N-end rule, which recognizes specific unacetylated Nt residues (Sriram et al., 2011). Eukaryotic proteins are synthesized with methionine (Met) at the N terminus, but new N termini can be generated via the action of endopeptidases or by cotranslational cleavage of Nt-Met by methionine aminopeptidases (MAPs). "
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    • "to produce a destabilizing N - terminal residue in proteins : 1 ) cleavage of proteins by endopeptidases in the cytosol , 2 ) removal of signaling or transit peptides , and 3 ) removal of the first Met residue by Met amino - peptidase . The latter occurs only if the second residue of a protein is small ( Ala , Cys , Gly , Pro , Ser , Thr , Val ) ( Sriram et al . , 2011 ) . Interestingly , proteins with a Cys residue at the second posi - tion can be processed by the N - end rule pathway in mammals and plants . Such a protein can become accessible to ATE1 / 2 after oxidation of the N - terminal Cys via an unknown mechanism and subsequently can be processed by the N - end rule pathway . The oxidation of "
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