1. Academic Validation
  2. Control of mammalian G protein signaling by N-terminal acetylation and the N-end rule pathway

Control of mammalian G protein signaling by N-terminal acetylation and the N-end rule pathway

  • Science. 2015 Mar 13;347(6227):1249-1252. doi: 10.1126/science.aaa3844.
Sang-Eun Park # 1 Jeong-Mok Kim # 1 Ok-Hee Seok 1 Hanna Cho 1 Brandon Wadas 2 Seon-Young Kim 3 4 Alexander Varshavsky 2 Cheol-Sang Hwang 1
Affiliations

Affiliations

  • 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 Medical Genomics Research Center, KRIBB, Daejeon, South Korea.
  • 4 Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea.
  • # Contributed equally.
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.

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