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

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Science  13 Mar 2015:
Vol. 347, Issue 6227, pp. 1249-1252
DOI: 10.1126/science.aaa3844

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The N-end rule finds a physiological function

The N-end–rule pathway for protein degradation is a canonical degradation pathway discovered in the 1980s. In recent years, studies have focused on finding novel variant pathways of N-end recognition. The “classical” pathway is blocked by N-terminal acetylation of the substrate. However, in yeast, N-terminal acetylation need not block degradation, because a second pathway can act on acetylated N-termini. But is this alternate pathway a major player in the physiology of mammals? Park et al. now confirm the existence of the alternate pathway in mammalian cells. Most notably, patient-derived point mutations thought to confer hypertension in humans affect susceptibility to this pathway for the encoded protein substrate, Rgs2.

Science, this issue p. 1249


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 Nα-terminal acetyl group.

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