Mechanism of beta-arrestin 1 mediated Src activation via Src SH3 domain revealed by cryo-electron microscopy

TL;DR

This paper reveals how beta-arrestin 1 activates the Src protein using structural insights from cryo-electron microscopy.

Contribution

The study provides the first structural mechanism of beta-arrestin 1-mediated Src activation through SH3 domain interactions.

Findings

Beta-arrestin 1 interacts with Src's SH3 domain via two distinct sites.

These interactions disrupt Src's autoinhibited state and trigger its activation.

The findings suggest beta-arrestin 1 functions as an active regulator, not just a scaffold.

Abstract

Beta-arrestins (βarrs) are key regulators and transducers of G-protein coupled receptor signaling; however, little is known of how βarrs communicate with their downstream effectors. Here, we delineate structural mechanisms underlying βarr-mediated signal transduction. Using cryo-electron microscopy, we elucidate how βarr1 recruits and activates the non-receptor tyrosine kinase Src, a well-established signaling partner of βarrs. βarr1 engages Src SH3 through two distinct sites, each employing a different recognition mechanism: a polyproline motif in the N-domain and a non-proline-based interaction in the central crest region. At both sites βarr1 interacts with the aromatic surface of SH3, disrupting the autoinhibited conformation of Src and directly triggering its allosteric activation. This structural evidence establishes βarr1 as an active regulatory protein rather than a passive scaffold and suggests a potentially general mechanism for βarr-mediated signaling across diverse effectors.

Beta-arrestins are key transducers of G-protein coupled receptors, but the mechanisms of beta-arrestin signaling are poorly understood. Here, authors use cryo-electron microscopy to show how beta-arrestin 1 binds and activates Src kinase

Figures