title: The N-terminal methionine of cellular proteins as a degradation signal.
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.
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, South Korea.
authors.forename: Heon-Ki
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, South Korea.
authors.forename: Ryu-Ryun
authors.initials: RR
authors.lastname: Kim
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Jang-Hyun
authors.initials: JH
authors.lastname: Oh
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, South Korea.
authors.forename: Hanna
authors.initials: H
authors.lastname: Cho
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: avarsh@caltech.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Varshavsky
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, South Korea. Electronic address: cshwang@postech.ac.kr.
authors.forename: Cheol-Sang
authors.initials: CS
authors.lastname: Hwang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D053858:Metabolic Networks and Pathways; D008715:Methionine / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D017510:Protein Folding; D021382:Protein Sorting Signals; D059748:Proteolysis; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D021382:Protein Sorting Signals; D029701:Saccharomyces cerevisiae Proteins; D008715:Methionine