8as3

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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.
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.
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A key GPCR phosphorylation motif discovered in arrestin2⋅CCR5 phosphopeptide complexes.,Isaikina P, Petrovic I, Jakob RP, Sarma P, Ranjan A, Baruah M, Panwalkar V, Maier T, Shukla AK, Grzesiek S Mol Cell. 2023 May 23:S1097-2765(23)00326-X. doi: 10.1016/j.molcel.2023.05.002. PMID:37244255<ref>PMID:37244255</ref>
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A key GPCR phosphorylation motif discovered in arrestin2⋅CCR5 phosphopeptide complexes.,Isaikina P, Petrovic I, Jakob RP, Sarma P, Ranjan A, Baruah M, Panwalkar V, Maier T, Shukla AK, Grzesiek S Mol Cell. 2023 Jun 15;83(12):2108-2121.e7. doi: 10.1016/j.molcel.2023.05.002. , Epub 2023 May 26. PMID:37244255<ref>PMID:37244255</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Current revision

Structure of arrestin2 in complex with 6P CCR5 phosphopeptide and Fab30

PDB ID 8as3

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