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Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide

Publication ,  Journal Article
Shukla, AK; Manglik, A; Kruse, AC; Xiao, K; Reis, RI; Tseng, WC; Staus, DP; Hilger, D; Uysal, S; Huang, LY; Paduch, M; Tripathi-Shukla, P ...
Published in: Nature
2013

The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second-messenger-generating enzymes and other effectors, GRKs phosphorylate activated receptors, and arrestins subsequently bind phosphorylated receptors and cause receptor desensitization. Arrestins activated by interaction with phosphorylated receptors can also mediate G-protein-independent signalling by serving as adaptors to link receptors to numerous signalling pathways. Despite their central role in regulation and signalling of GPCRs, a structural understanding of β-arrestin activation and interaction with GPCRs is still lacking. Here we report the crystal structure of β-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). This peptide has previously been shown to functionally and conformationally activate β-arrestin-1 (ref. 5). To capture this active conformation, we used a conformationally selective synthetic antibody fragment (Fab30) that recognizes the phosphopeptide-activated state of β-arrestin-1. The structure of the β-arrestin-1-V2Rpp-Fab30 complex shows marked conformational differences in β-arrestin-1 compared to its inactive conformation. These include rotation of the amino-and carboxy-terminal domains relative to each other, and a major reorientation of the 'lariat loop' implicated in maintaining the inactive state of β-arrestin-1. These results reveal, at high resolution, a receptor-interacting interface on β-arrestin, and they indicate a potentially general molecular mechanism for activation of these multifunctional signalling and regulatory proteins. © 2013 Macmillan Publishers Limited. All rights reserved.

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Published In

Nature

DOI

ISSN

0028-0836

Publication Date

2013

Volume

497

Issue

7447

Start / End Page

137 / 141

Related Subject Headings

  • General Science & Technology
 

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Shukla, A. K., Manglik, A., Kruse, A. C., Xiao, K., Reis, R. I., Tseng, W. C., … Lefkowitz, R. J. (2013). Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature, 497(7447), 137–141. https://doi.org/10.1038/nature12120
Shukla, A. K., A. Manglik, A. C. Kruse, K. Xiao, R. I. Reis, W. C. Tseng, D. P. Staus, et al. “Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide.” Nature 497, no. 7447 (2013): 137–41. https://doi.org/10.1038/nature12120.
Shukla AK, Manglik A, Kruse AC, Xiao K, Reis RI, Tseng WC, et al. Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature. 2013;497(7447):137–41.
Shukla, A. K., et al. “Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide.” Nature, vol. 497, no. 7447, 2013, pp. 137–41. Scival, doi:10.1038/nature12120.
Shukla AK, Manglik A, Kruse AC, Xiao K, Reis RI, Tseng WC, Staus DP, Hilger D, Uysal S, Huang LY, Paduch M, Tripathi-Shukla P, Koide A, Koide S, Weis WI, Kossiakoff AA, Kobilka BK, Lefkowitz RJ. Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature. 2013;497(7447):137–141.
Journal cover image

Published In

Nature

DOI

ISSN

0028-0836

Publication Date

2013

Volume

497

Issue

7447

Start / End Page

137 / 141

Related Subject Headings

  • General Science & Technology