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

Park, Sang-Eun and Kim, Jeong-Mok and Seok, Ok-Hee and Cho, Hanna and Wadas, Brandon and Kim, Seon-Young and Varshavsky, Alexander and Hwang, Cheol-Sang (2015) Control of mammalian G protein signaling by N-terminal acetylation and the N-end rule pathway. Science, 347 (6227). pp. 1249-1252. ISSN 0036-8075. PMCID PMC4748709.

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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 Nα-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.

Item Type:Article
Related URLs:
URLURL TypeDescription 10.1126/science.aaa3844DOIArticle Materials CentralArticle
Kim, Jeong-Mok0000-0002-7223-248X
Varshavsky, Alexander0000-0002-4011-258X
Hwang, Cheol-Sang0000-0002-0105-5957
Additional Information:© 2015 American Association for the Advancement of Science. Received for publication 27 November 2014. Accepted for publication 6 February 2015. We thank R. Neubig, M. Mulvihill, and E. Wiertz for gifts of plasmids, and K. Piatkov for helpful suggestions. Supported by grants from the National Research Foundation of the Korea government (MSIP) (NRF-2011-0021975, NRF-2012R1A4A1028200, NRF-2013R1A1A2012529) and BK21 Plus Program (C.-S.H.), and by NIH grants DK039520 and GM031530 (A.V.).
Funding AgencyGrant Number
National Research Foundation KoreaNRF-2011-0021975
National Research Foundation KoreaNRF-2012R1A4A1028200
National Research Foundation KoreaNRF-2013R1A1A2012529
Issue or Number:6227
PubMed Central ID:PMC4748709
Record Number:CaltechAUTHORS:20150316-112138335
Persistent URL:
Official Citation:Control of mammalian G protein signaling by N-terminal acetylation and the N-end rule pathway Sang-Eun Park, Jeong-Mok Kim, Ok-Hee Seok, Hanna Cho, Brandon Wadas, Seon-Young Kim, Alexander Varshavsky, and Cheol-Sang Hwang Science 13 March 2015: 347 (6227), 1249-1252. [DOI:10.1126/science.aaa3844]
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:55786
Deposited By: Tony Diaz
Deposited On:16 Mar 2015 19:33
Last Modified:09 Mar 2020 13:18

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