Structures of rhodopsin in complex with G-protein-coupled receptor kinase 1

Authors

Qiuyan Chen, Purdue University
Manolo Plascencia, University of Michigan - Ann Arbor
Zhuang Li, Purdue University
Somnath Mukherjee, University of Chicago
Dhabaleswar Patra, Purdue University
Chun-Liang Chen, Purdue University
Thomas Klose, Purdue University
Xin-Qiu Joe Yao, University of Nebraska at OmahaFollow
Anthony A. Kossiakoff, University of Chicago
Leifu Chang, Purdue University
Philip C. Andrews, University of Michigan - Ann Arbor
John J.G. Tesmer, Purdue University

Author ORCID Identifier

Yao - https://orcid.org/0000-0003-2706-2028

Document Type

Article

Publication Date

7-14-2021

Publication Title

Nature

Volume

595

First Page

600

Last Page

605

DOI

https://doi.org/10.1038/s41586-021-03721-x

Abstract

G-protein-coupled receptor (GPCR) kinases (GRKs) selectively phosphorylate activated GPCRs, thereby priming them for desensitization1. Although it is unclear how GRKs recognize these receptors2,3,4, a conserved region at the GRK N terminus is essential for this process5,6,7,8. Here we report a series of cryo-electron microscopy single-particle reconstructions of light-activated rhodopsin (Rho*) bound to rhodopsin kinase (GRK1), wherein the N terminus of GRK1 forms a helix that docks into the open cytoplasmic cleft of Rho*. The helix also packs against the GRK1 kinase domain and stabilizes it in an active configuration. The complex is further stabilized by electrostatic interactions between basic residues that are conserved in most GPCRs and acidic residues that are conserved in GRKs. We did not observe any density for the regulator of G-protein signalling homology domain of GRK1 or the C terminus of rhodopsin. Crosslinking with mass spectrometry analysis confirmed these results and revealed dynamic behaviour in receptor-bound GRK1 that would allow the phosphorylation of multiple sites in the receptor tail. We have identified GRK1 residues whose mutation augments kinase activity and crosslinking with Rho*, as well as residues that are involved in activation by acidic phospholipids. From these data, we present a general model for how a small family of protein kinases can recognize and be activated by hundreds of different GPCRs.

Comments

This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1038/s41586-021-03721-x

Publisher holds a Bespoken License

Recommended Citation

Chen, Q., Plasencia, M., Li, Z. et al. Structures of rhodopsin in complex with G-protein-coupled receptor kinase 1. Nature 595, 600–605 (2021). https://doi.org/10.1038/s41586-021-03721-x