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Selective integrin endocytosis is driven by interactions between the integrin α-chain and AP2.

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De Franceschi, Nicola 
Arjonen, Antti 
Elkhatib, Nadia 
Denessiouk, Konstantin 
Wrobel, Antoni G 


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.



Adaptor Protein Complex 2, Amino Acid Motifs, Amino Acid Sequence, Cell Adhesion, Cell Movement, Endocytosis, Humans, Integrin alpha2, Integrin alpha4, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Multimerization, Protein Structure, Tertiary, Sequence Alignment

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Nat Struct Mol Biol

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Springer Science and Business Media LLC
Wellcome Trust (090909/Z/09/Z)
Wellcome Trust (097040/Z/11/Z)
We gratefully acknowledge the following funding sources: N.d.F. FinPharma Doctoral Program, Instrumentarium Foundation, Orion Research Foundation, Liv och Halsa foundation, Finsk-Norska Medicinska Stiftelsen and the Magnus Ehrnrooth Foundation; J.I. Academy of Finland CoE, European Research Council Consolidator Grant, the Sigrid Juselius Foundation, The Finnish Heart Foundation and Finnish Cancer Organizations. DJO, AGW and TW are funded by Wellcome Trust fellowship 090909 (DJO).