N-Terminal Acetylation and the N-End Rule Proteolytic System for the Control of G ProteinSignaling
* SPEAKERS
Name
Affiliation
E-mail
Cheol-Sang Hwang
POSTECH
* HOST(Applicant)
Name
Affiliation
E-mail
Junghyo Jo
APCTP
jojunghyo(at)apctp.org
* DATE / TIME
2015-04-10, 11:00am
* ABSTRACT
The N-end rule pathway recognizes proteins containing N-terminal degradation signals for the proteolytic system, thusplaying a wide range of biological functions. The N-end rule pathway comprises two branches: the Arg/N-end rule pathway and the Ac/N-end rule pathway. The Arg/N-end rule pathway targets proteins with specific unacetylated N-terminal residues, whereas the Ac/N-end rule pathway targets proteins with Nα-terminally acetylated residues (Hwang CS et al, Science, 2010).We recently discovered that the complementarity of the Arg/N-end rule and Ac/N-end rule pathways enables the elimination of both an Nt-acetylated protein and its unacetylated counterpart(Kim HK et al, Cell, 2014). The Ac/N-end rule pathway has been characterized in S. cerevisiae (Shemorry A et al, Mol Cell, 2013; Kim HK et al, Cell, 2014), but its presence in mammals has been conjectural so far.
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 compared to people expressing wild-type Met-Gln-Rgs2 (MQ-Rgs2). Here we found that wild-typeMQ-Rgs2 and its mutant MR-Rgs2 were destroyed by the Ac/N‑end rule pathway. The shortest-lived mutant ML‑Rgs2 was targeted by both the Ac/N-end rule and Arg/N-end rule pathways. Thus, the Nt-acetylated Ac‑MX‑Rgs2 (X=Q, L, R) 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 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.
