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Published January 16, 2014 | Supplemental Material + Accepted Version
Journal Article Open

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


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.

Additional Information

© 2014 Elsevier Inc. Available online 19 December . In Press, Corrected Proof, Note to users. Received: September 7, 2013. Revised: September 26, 2013. Accepted: November 20, 2013. Published: December 19, 2013. We thank S.-Y. Kim (Korea Research, Institute of Biosciences and Biotechnology) for calculating the relative content of encoded human Met-V proteins, and D.H. Wolf (University of Stuttgart, Germany) for providing pFE15. We also thank C. Brower, K. Piatkov, J. Raskatov and B. Wadas (California Institute of Technology), and I. Hwang (Pohang University of Science and Technology) for helpful comments on the manuscript. We are grateful to members of the Hwang and Varshavsky laboratories for their assistance and advice. This work was supported by grants to C.-S.H from the National Research Foundation (NRF) of the Korea government (MSIP) (NRF-2011-0021975 and NRF-2012R1A4A1028200), the Korean Healthcare Technology R&D Project of the Ministry of Health & Welfare (HI11C1279), and the T.J. Park Science Fellowship of POSCO T.J. Park Foundation, and also by grants to A.V. from the U.S. National Institutes of Health (DK039520 and GM031530). H.-K.K was supported by the Korean Government's NRF-2013-Global Ph.D. Fellowship Program (NRF-2013H1A2A1033225) and the BK21 PLUS Program.

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Accepted Version - nihms551979.pdf

Supplemental Material - mmc1.pdf


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August 19, 2023
October 25, 2023