Molecular mechanism of modulating arrestin conformation by GPCR phosphorylation

Andrija Sente, Raphael Peer, Ashish Srivastava, Mithu Baidya, Arthur M. Lesk, Santhanam Balaji, Arun K. Shukla, M. Madan Babu, Tilman Flock

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Arrestins regulate the signaling of ligand-activated, phosphorylated G-protein-coupled receptors (GPCRs). Different patterns of receptor phosphorylation (phosphorylation barcode) can modulate arrestin conformations, resulting in distinct functional outcomes (for example, desensitization, internalization, and downstream signaling). However, the mechanism of arrestin activation and how distinct receptor phosphorylation patterns could induce different conformational changes on arrestin are not fully understood. We analyzed how each arrestin amino acid contributes to its different conformational states. We identified a conserved structural motif that restricts the mobility of the arrestin finger loop in the inactive state and appears to be regulated by receptor phosphorylation. Distal and proximal receptor phosphorylation sites appear to selectively engage with distinct arrestin structural motifs (that is, micro-locks) to induce different arrestin conformations. These observations suggest a model in which different phosphorylation patterns of the GPCR C terminus can combinatorially modulate the conformation of the finger loop and other phosphorylation-sensitive structural elements to drive distinct arrestin conformation and functional outcomes.

Original languageEnglish (US)
Pages (from-to)538-545
Number of pages8
JournalNature Structural and Molecular Biology
Volume25
Issue number6
DOIs
StatePublished - Jun 1 2018

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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