4JQI

Structure of active beta-arrestin1 bound to a G protein-coupled receptor phosphopeptide

Summary for 4JQI

• Entry DOI: 10.2210/pdb4jqi/pdb
• Descriptor: Beta-arrestin-1, Fab30 heavy chain, Fab30 light chain, ... (8 entities in total)
• Functional Keywords: arrestin, gpcr, g-protein coupled receptor, signaling, signaling protein
• Biological source: Rattus norvegicus (brown rat,rat,rats); More
• Cellular location: Cytoplasm: P29066; Cell membrane; Multi-pass membrane protein: 4JQI
• Total number of polymer chains: 4
• Total formula weight: 98112.13

Authors

Shukla, A.K.,Manglik, A.,Kruse, A.C.,Xiao, K.,Reis, R.I.,Tseng, W.C.,Staus, D.P.,Hilger, D.,Uysal, S.,Huang, L.H.,Paduch, M.,Shukla, P.T.,Koide, A.,Koide, S.,Weis, W.I.,Kossiakoff, A.A.,Kobilka, B.K.,Lefkowitz, R.J. (deposition date: 2013-03-20, release date: 2013-04-17, Last modification date: 2024-10-16)

Primary citation

Shukla, A.K.,Manglik, A.,Kruse, A.C.,Xiao, K.,Reis, R.I.,Tseng, W.C.,Staus, D.P.,Hilger, D.,Uysal, S.,Huang, L.Y.,Paduch, M.,Tripathi-Shukla, P.,Koide, A.,Koide, S.,Weis, W.I.,Kossiakoff, A.A.,Kobilka, B.K.,Lefkowitz, R.J.
Structure of active beta-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide.
Nature, 497:137-141, 2013

PubMed Abstract: 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.

PubMed: 23604254
DOI: 10.1038/nature12120

Experimental method

X-RAY DIFFRACTION (2.6 Å)