Selective integrin endocytosis is driven by α chain:AP2 interactions
de, Franceschi Nicola
Wilson, Thomas A
Novel integrin endocytosis motif
Nature Structural & Molecular Biology
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de, F. N., Arjonen, A., Elkhatib, N., Debessiouk, K., Wrobel, A., Wilson, T. A., Pouwels, J., et al. (2016). Selective integrin endocytosis is driven by α chain:AP2 interactions. Nature Structural & Molecular Biology, 23 172-179. https://doi.org/10.1038/nsmb.3161
Integrins are heterodimeric, cell-surface adhesion molecules comprised of one of 18 a-chains and one of 8 b-chains which control a range of cell functions in a matrix and ligand specific manner. Integrins can be internalised by clathrin-mediated endocytosis (CME) using b-subunit based motifs found in all integrin heterodimers. Whether selective CME also applies to specific integrin heterodimers was unknown. We found that a subset of a-subunits harbour an evolutionarily conserved and functional YxxF motif directing integrins to selective internalisation by the most abundant endocytic clathrin adaptor AP2. We determined the structure of the human (homo sapiens) integrin a4-tail motif in complex with AP2 C-m2 and confirmed the binding by ITC. 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.
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).
Wellcome Trust (090909/Z/09/Z)
Wellcome Trust (097040/Z/11/Z)
External DOI: https://doi.org/10.1038/nsmb.3161
This record's URL: https://www.repository.cam.ac.uk/handle/1810/253175