8HST

The structure of rat beta-arrestin1

Summary for 8HST

• Entry DOI: 10.2210/pdb8hst/pdb
• Descriptor: Beta-arrestin-1 (2 entities in total)
• Functional Keywords: arrestin, signaling protein
• Biological source: Rattus norvegicus (Norway rat)
• Total number of polymer chains: 2
• Total formula weight: 93011.62

Authors

Yun, Y.,Yoon, H.J.,Choi, Y.,Lee, H.H. (deposition date: 2022-12-20, release date: 2023-07-19, Last modification date: 2024-05-29)

Primary citation

Yun, Y.,Yoon, H.J.,Jeong, Y.,Choi, Y.,Jang, S.,Chung, K.Y.,Lee, H.H.
GPCR targeting of E3 ubiquitin ligase MDM2 by inactive beta-arrestin.
Proc.Natl.Acad.Sci.USA, 120:e2301934120-e2301934120, 2023

PubMed 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 peptide. The acidic residues of Mdm2 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 binding to β-arrestin1 induces the interdomain interface to be more dynamic and uncouples the IP-induced oligomer of β-arrestin1. These results show how the E3 ligase, Mdm2, interacts with β-arrestins to promote the internalization of GPCRs.

PubMed: 37399373
DOI: 10.1073/pnas.2301934120

Experimental method

X-RAY DIFFRACTION (2.66 Å)