title: The conserved isoleucine-valine-phenylalanine motif couples activation state and endocytic functions of beta-arrestins.
abstract: Beta-arrestins (betaarrs) play a central role in the regulation of G-protein-coupled receptors (GPCRs). Their binding to phosphorylated activated GPCRs induces a conformational transition to an active state resulting in the release of their flexible C-terminal tail. Binding sites for clathrin and the adaptor protein (AP)-2 clathrin adaptor complex are then unmasked, which drive the recruitment of betaarrs-GPCR complexes into clathrin-coated pits (CCPs). A conserved isoleucine-valine-phenylalanine (IVF) motif of the C-terminal tail controls betaarr activation through intramolecular interactions. Here, we provide structural, biochemical and functional evidence in living cells that the IVF motif also controls binding to AP-2. While the F residue is directly involved in AP-2 binding, substitutions of I and V residues, markedly enhanced affinity for AP-2 resulting in active betaarr mutants, which are constitutively targeted to CCPs in the absence of any GPCR activation. Conformational change and endocytic functions of betaarrs thus appear to be coordinated via the complex molecular interactions established by the IVF motif.
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Burtey
authors.forename: Eva M
authors.initials: EM
authors.lastname: Schmid
authors.forename: Marijn G J
authors.initials: MG
authors.lastname: Ford
authors.forename: Joshua Z
authors.initials: JZ
authors.lastname: Rappoport
authors.forename: Mark G H
authors.initials: MG
authors.lastname: Scott
authors.forename: Stefano
authors.initials: S
authors.lastname: Marullo
authors.forename: Sanford M
authors.initials: SM
authors.lastname: Simon
authors.forename: Harvey T
authors.initials: HT
authors.lastname: McMahon
authors.forename: Alexandre
authors.initials: A
authors.lastname: Benmerah
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019390:Arrestins / Q000737:chemistry*; D019556:COS Cells; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D006367:HeLa Cells; D006801:Humans; D007532:Isoleucine / Q000737:chemistry*; D008969:Molecular Sequence Data; D010649:Phenylalanine / Q000737:chemistry*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014633:Valine / Q000737:chemistry*; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; D007532:Isoleucine; D010649:Phenylalanine; D014633:Valine