Molecular mechanism of GPCR-mediated arrestin activation

Naomi R. Latorraca, Jason K. Wang, Brian Bauer, Raphael J. L. Townshend, Scott A. Hollingsworth, Julia E. Olivieri, H. Eric Xu, Martha E. Sommer () and Ron O. Dror ()
Additional contact information
Naomi R. Latorraca: Stanford University
Jason K. Wang: Stanford University
Brian Bauer: Charité-Universitätsmedizin Berlin
Raphael J. L. Townshend: Stanford University
Scott A. Hollingsworth: Stanford University
Julia E. Olivieri: Stanford University
H. Eric Xu: Chinese Academy of Sciences
Martha E. Sommer: Charité-Universitätsmedizin Berlin
Ron O. Dror: Stanford University

Nature, 2018, vol. 557, issue 7705, 452-456

Abstract: 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 unclear1,2. 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.

Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (6)

Downloads: (external link)
https://www.nature.com/articles/s41586-018-0077-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:557:y:2018:i:7705:d:10.1038_s41586-018-0077-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-018-0077-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().