title: Selective integrin endocytosis is driven by interactions between the integrin α-chain and AP2.
abstract: Integrins are heterodimeric cell-surface adhesion molecules comprising one of 18 possible α-chains and one of eight possible β-chains. They control a range of cell functions in a matrix- and ligand-specific manner. Integrins can be internalized by clathrin-mediated endocytosis (CME) through β subunit-based motifs found in all integrin heterodimers. However, whether specific integrin heterodimers can be selectively endocytosed was unknown. Here, we found that a subset of α subunits contain an evolutionarily conserved and functional YxxΦ motif directing integrins to selective internalization by the most abundant endocytic clathrin adaptor, AP2. We determined the structure of the human integrin α4-tail motif in complex with the AP2 C-μ2 subunit and confirmed the interaction by isothermal titration calorimetry. Mutagenesis of the motif impaired selective heterodimer endocytosis and attenuated integrin-mediated cell migration. We propose that integrins evolved to enable selective integrin-receptor turnover in response to changing matrix conditions.
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Franceschi
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Arjonen
authors.affiliation: Institut Gustave Roussy, Villejuif, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), U1170, Villejuif, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Elkhatib
authors.affiliation: Department of Biosciences, Åbo Akademi University, Turku, Finland.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Denessiouk
authors.affiliation: Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Antoni G
authors.initials: AG
authors.lastname: Wrobel
authors.affiliation: Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wilson
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Jeroen
authors.identifier: http://orcid.org/0000-0002-5388-6103
authors.initials: J
authors.lastname: Pouwels
authors.affiliation: Institut Gustave Roussy, Villejuif, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), U1170, Villejuif, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Montagnac
authors.affiliation: Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Owen
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, Finland.|Department of Biochemistry and Food Chemistry, University of Turku, Turku, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000737:chemistry / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002448:Cell Adhesion; D002465:Cell Movement; D004705:Endocytosis; D006801:Humans; D039421:Integrin alpha2 / Q000737:chemistry / Q000378:metabolism*; D039441:Integrin alpha4 / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D033962:Adaptor Protein Complex 2; D039421:Integrin alpha2; D039441:Integrin alpha4