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A key GPCR phosphorylation motif discovered in arrestin2⋅CCR5 phosphopeptide complexes

Isaikina, Polina and Petrovic, Ivana and Jakob, Roman P. and Sarma, Parishmita and Ranjan, Ashutosh and Baruah, Minakshi and Panwalkar, Vineet and Maier, Timm and Shukla, Arun K. and Grzesiek, Stephan. (2023) A key GPCR phosphorylation motif discovered in arrestin2⋅CCR5 phosphopeptide complexes. Molecular cell, 83 (12). pp. 2108-2121.e7.

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Abstract

The two non-visual arrestins, arrestin2 and arrestin3, bind hundreds of GPCRs with different phosphorylation patterns, leading to distinct functional outcomes. Structural information on these interactions is available only for very few GPCRs. Here, we have characterized the interactions between the phosphorylated human CC chemokine receptor 5 (CCR5) and arrestin2. We identified several new CCR5 phosphorylation sites necessary for stable arrestin2 complex formation. Structures of arrestin2 in the apo form and complexes with CCR5 C-terminal phosphopeptides, together with NMR, biochemical, and functional assays, revealed three phosphoresidues in a pXpp motif that are essential for arrestin2 binding and activation. The identified motif appears responsible for robust arrestin2 recruitment in many other GPCRs. An analysis of receptor sequences and available structural and functional information provides hints on the molecular basis of arrestin2/arrestin3 isoform specificity. Our findings demonstrate how multi-site phosphorylation controls GPCR⋅arrestin interactions and provide a framework to probe the intricate details of arrestin signaling.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Grzesiek)
05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Maier)
UniBasel Contributors:Grzesiek, Stephan and Petrovic, Ivana and Jakob, Roman Peter and Maier, Timm and Isaikina, Polina and Panwalkar, Vineet
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
ISSN:1097-2765
e-ISSN:1097-4164
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:26 May 2024 01:30
Deposited On:12 Jun 2023 09:31

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