GPCR targeting of E3 ubiquitin ligase MDM2 by inactive β-arrestin

Abstract

E3 ubiquitin ligase Mdm2 facilitates β-arrestin ubiquitination, leading to the internalization of G protein–coupled receptors (GPCRs). In this process, β-arrestins bind to Mdm2 and recruit it to the receptor; however, the molecular architecture of the β-arrestin-Mdm2 complex has not been elucidated yet. Here, we identified the β-arrestin-binding region (ABR) on Mdm2 and solved the crystal structure of β-arrestin1 in complex with Mdm2 ABR peptide. The acidic residues of Mdm2 ABR bind to the positively charged concave side of the β-arrestin1 N-domain. The C-tail of β-arrestin1 is still bound to the N-domain, indicating that Mdm2 binds to the inactive state of β-arrestin1, whereas the phosphorylated C-terminal tail of GPCRs binds to activate β-arrestins. The overlapped binding site of Mdm2 and GPCR C-tails on β-arrestin1 suggests that the binding of GPCR C-tails might trigger the release of Mdm2. Moreover, hydrogen/deuterium exchange experiments further show that Mdm2 ABR binding to β-arrestin1 induces the interdomain interface to be more dynamic and uncouples the IP 6 -induced oligomer of β-arrestin1. These results show how the E3 ligase, Mdm2, interacts with β-arrestins to promote the internalization of GPCRs.

BRD4 promotes gouty arthritis through MDM2-mediated PPARγ degradation and pyroptosis

“…The present investigation may elucidate the mechanism for PPARγ ubiquitination in GA and isolate the specific E3 ubiquitin ligase responsible for this modulation. Mouse double minute 2 (MDM2) is a suppressor of oncoprotein p53 (Yun et al 2023 ). Notably, MDM2 is involved in regulating the development of various disease by acting as an E3 ubiquitin ligase.…”