Molecular mechanism of GPCR-mediated arrestin activation

Department

Computer Science

Document Type

Article

Publication Title

Nature

ISSN

0028-0836

Volume

557

Issue

7705

DOI

10.1038/s41586-018-0077-3

First Page

452

Last Page

456

Publication Date

5-17-2018

Abstract

Despite intense interest in discovering drugs that cause G-protein-coupled receptors (GPCRs) to selectively stimulate or block arrestin signalling, the structural mechanism of receptor-mediated arrestin activation remains unclear 1,2 . Here we reveal this mechanism through extensive atomic-level simulations of arrestin. We find that the receptor's transmembrane core and cytoplasmic tail - which bind distinct surfaces on arrestin - can each independently stimulate arrestin activation. We confirm this unanticipated role of the receptor core, and the allosteric coupling between these distant surfaces of arrestin, using site-directed fluorescence spectroscopy. The effect of the receptor core on arrestin conformation is mediated primarily by interactions of the intracellular loops of the receptor with the arrestin body, rather than the marked finger-loop rearrangement that is observed upon receptor binding. In the absence of a receptor, arrestin frequently adopts active conformations when its own C-Terminal tail is disengaged, which may explain why certain arrestins remain active long after receptor dissociation. Our results, which suggest that diverse receptor binding modes can activate arrestin, provide a structural foundation for the design of functionally selective ('biased') GPCR-Targeted ligands with desired effects on arrestin signalling.

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