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

Nature Structural & Molecular Biology
Nicola De FranceschiJohanna Ivaska

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.

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Citations

Jan 7, 2017·Cell Adhesion & Migration·Thomas GrewalCarles Rentero
Feb 9, 2017·Nature Structural & Molecular Biology·Nicola De FranceschiJohanna Ivaska
Mar 30, 2017·Proceedings of the National Academy of Sciences of the United States of America·Joel B HeimAlexander Meves
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May 12, 2019·Journal of Cell Science·Pranshu SahgalJohanna Ivaska
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