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

Nat Struct Mol Biol. 2016 Feb;23(2):172-9. doi: 10.1038/nsmb.3161. Epub 2016 Jan 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Adaptor Protein Complex 2
  • Integrin alpha2
  • Integrin alpha4