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Cell. 2014 Jan 16;156(1-2):158-69. doi: 10.1016/j.cell.2013.11.031. Epub 2013 Dec 19.

The N-terminal methionine of cellular proteins as a degradation signal.

Author information

1
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, South Korea.
2
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
3
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: avarsh@caltech.edu.
4
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, South Korea. Electronic address: cshwang@postech.ac.kr.

Abstract

The Arg/N-end rule pathway targets for degradation proteins that bear specific unacetylated N-terminal residues while the Ac/N-end rule pathway targets proteins through their N(α)-terminally acetylated (Nt-acetylated) residues. Here, we show that Ubr1, the ubiquitin ligase of the Arg/N-end rule pathway, recognizes unacetylated N-terminal methionine if it is followed by a hydrophobic residue. This capability of Ubr1 expands the range of substrates that can be targeted for degradation by the Arg/N-end rule pathway because virtually all nascent cellular proteins bear N-terminal methionine. We identified Msn4, Sry1, Arl3, and Pre5 as examples of normal or misfolded proteins that can be destroyed through the recognition of their unacetylated N-terminal methionine. Inasmuch as proteins bearing the Nt-acetylated N-terminal methionine residue are substrates of the Ac/N-end rule pathway, the resulting complementarity of the Arg/N-end rule and Ac/N-end rule pathways enables the elimination of protein substrates regardless of acetylation state of N-terminal methionine in these substrates.

PMID:
24361105
PMCID:
PMC3988316
DOI:
10.1016/j.cell.2013.11.031
[Indexed for MEDLINE]
Free PMC Article

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