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Published March 13, 2015 | public
Journal Article Open

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


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.

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.).

Attached Files

Supplemental Material - Park.SM.pdf

Accepted Version - nihms-755483.pdf


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August 20, 2023
August 20, 2023