title: Control of mammalian G protein signaling by N-terminal acetylation and the N-end rule pathway.
abstract: Rgs2, a regulator of G proteins, lowers blood pressure by decreasing signaling through Gαq. Human patients expressing Met-Leu-Rgs2 (ML-Rgs2) or Met-Arg-Rgs2 (MR-Rgs2) are hypertensive relative to people expressing wild-type Met-Gln-Rgs2 (MQ-Rgs2). We found that wild-type MQ-Rgs2 and its mutant, MR-Rgs2, were destroyed by the Ac/N-end rule pathway, which recognizes N(α)-terminally acetylated (Nt-acetylated) proteins. The shortest-lived mutant, ML-Rgs2, was targeted by both the Ac/N-end rule and Arg/N-end rule pathways. The latter pathway recognizes unacetylated N-terminal residues. Thus, the Nt-acetylated Ac-MX-Rgs2 (X = Arg, Gln, Leu) proteins are specific substrates of the mammalian Ac/N-end rule pathway. Furthermore, the Ac/N-degron of Ac-MQ-Rgs2 was conditional, and Teb4, an endoplasmic reticulum (ER) membrane-embedded ubiquitin ligase, was able to regulate G protein signaling by targeting Ac-MX-Rgs2 proteins for degradation through their N(α)-terminal acetyl group.
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, South Korea.
authors.forename: Sang-Eun
authors.initials: SE
authors.lastname: Park
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, South Korea.
authors.forename: Jeong-Mok
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, South Korea.
authors.forename: Ok-Hee
authors.initials: OH
authors.lastname: Seok
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.
authors.forename: Brandon
authors.initials: B
authors.lastname: Wadas
authors.affiliation: Medical Genomics Research Center, KRIBB, Daejeon, South Korea.|Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea.
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
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.
authors.forename: Cheol-Sang
authors.initials: CS
authors.lastname: Hwang
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D059748:Proteolysis; D020710:RGS Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D008565:Membrane Proteins; D050505:Mutant Proteins; D020710:RGS Proteins; C087182:RGS2 protein, human; C504816:MARCHF6 protein, human; D044767:Ubiquitin-Protein Ligases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11