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The Conserved Isoleucine–Valine–Phenylalanine Motif Couples Activation State and Endocytic Functions of β‐Arrestins
Author(s) -
Burtey Anne,
Schmid Eva M.,
Ford Marijn G. J.,
Rappoport Joshua Z.,
Scott Mark G. H.,
Marullo Stefano,
Simon Sanford M.,
McMahon Harvey T.,
Benmerah Alexandre
Publication year - 2007
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1600-0854.2007.00578.x
Subject(s) - endocytic cycle , g protein coupled receptor , biology , signal transducing adaptor protein , microbiology and biotechnology , clathrin , biochemistry , receptor , phosphorylation , endocytosis , signal transduction
Beta‐arrestins (βarrs) 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 βarrs‐GPCR complexes into clathrin‐coated pits (CCPs). A conserved isoleucine‐valine‐phenylalanine (IVF) motif of the C‐terminal tail controls βarr 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 βarr mutants, which are constitutively targeted to CCPs in the absence of any GPCR activation. Conformational change and endocytic functions of βarrs thus appear to be coordinated via the complex molecular interactions established by the IVF motif.