The N-Terminal Methionine of Cellular Proteins as a Degradation Signal

Kim, Heonki; Kim, Ryu-Ryun; Oh, Jang-Hyun; Cho, Hanna; Varshavsky, Alexander; Hwang, Cheol-Sang

doi:10.1016/j.cell.2013.11.031

Cited by 151 publications

(213 citation statements)

References 102 publications

(89 reference statements)

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“…It was recently shown that both yeast and mammalian Ubr1 can recognize not only the unacetylated primary destabilizing N-terminal residues cited above, but also the unacetylated N-terminal Met residue, if it is followed by a hydrophobic residue. This capability of the Arg/N-end rule pathway greatly expands the range of its substrates, as virtually all nascent proteins bear N-terminal Met (23).…”

Section: Significancementioning

confidence: 99%

“…One of them, called the Arg/N-end rule pathway, targets specific unacetylated N-terminal residues (Fig. 1A) (11,15,23). The primary destabilizing N-terminal residues Arg, Lys, His, Leu, Phe, Tyr, Trp, and Ile are directly recognized by N-recognins.…”

Section: Significancementioning

confidence: 99%

“…1B) (17,23,24). The degradation signals and E3 Ub ligases of the Ac/N-end rule pathway are called Ac/N-degrons and Ac/N-recognins, respectively.…”

Section: Significancementioning

confidence: 99%

“…1) (9,11,12,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). The main determinant of an N-degron is a destabilizing N-terminal residue of a protein.…”

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confidence: 99%

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Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway

Piatkov

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Calpains are Ca 2+ -dependent intracellular proteases. We show here that calpain-generated natural C-terminal fragments of proteins that include G protein-coupled receptors, transmembrane ion channels, transcriptional regulators, apoptosis controllers, kinases, and phosphatases (Phe-GluN2a, Lys-Ica512, Arg-Ankrd2, Tyr-Grm1, Arg-Atp2b2, Glu-Bak, Arg-Igfbp2, Glu-IκBα, and Arg-cFos), are short-lived substrates of the Arg/N-end rule pathway, which targets destabilizing N-terminal residues. We also found that the identity of a fragment's N-terminal residue can change during evolution, but the residue's destabilizing activity is virtually always retained, suggesting selection pressures that favor a short half-life of the calpain-generated fragment. It is also shown that a self-cleavage of a calpain can result in an N-end rule substrate. Thus, the autoprocessing of calpains can control them by making active calpains short-lived. These and related results indicate that the Arg/N-end rule pathway mediates the remodeling of oligomeric complexes by eliminating protein fragments that are produced in these complexes through cleavages by calpains or other nonprocessive proteases. We suggest that this capability of the Arg/N-end rule pathway underlies a multitude of its previously known but mechanistically unclear functions.proteolysis | calpain substrates | ubiquitin

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Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 2 more Smart Citations

Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway

Piatkov

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Conversely, the Arg/N-end rule pathway targets specific un-acetylated N-terminal residues (Arg, Phe, Lys, Leu, His, Tyr, Trp, and Ile) and N-terminal Asn and Gln which have been deaminated and then Arginylated 14 . Un-acetylated N-terminal Met followed by a hydrophobic residue are also targeted for degradation by the Arg/N-end rule pathway 15 . Protein N-terminal acetylation is thought to be relevant to cancer development with NATs acting as tumour suppressors in healthy tissues and oncoproteins in cancerous cells 16 .…”

Section: Introductionmentioning

confidence: 99%

Novel IEF Peptide Fractionation Method Reveals a Detailed Profile of N-Terminal Acetylation in Chemotherapy-Responsive and -Resistant Ovarian Cancer Cells

et al. 2016

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Discovery of the Biology of the Ubiquitin System

Varshavsky

2014

JAMA

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The N-Terminal Methionine of Cellular Proteins as a Degradation Signal

Cited by 151 publications

References 102 publications

Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway

Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway

Novel IEF Peptide Fractionation Method Reveals a Detailed Profile of N-Terminal Acetylation in Chemotherapy-Responsive and -Resistant Ovarian Cancer Cells

Discovery of the Biology of the Ubiquitin System

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