Structural Basis of Paxillin Recruitment by Kindlin-2 in Regulating Cell Adhesion

Structure. 2019 Nov 5;27(11):1686-1697.e5. doi: 10.1016/j.str.2019.09.006. Epub 2019 Oct 4.

Abstract

Activation of cell surface receptor integrin has been extensively studied as the first key step to trigger cell adhesion, but the subsequent events, widely regarded as integrin "outside-in" signaling to form supramolecular complexes (focal adhesions [FAs]) to promote dynamic cell adhesion, remain poorly elucidated. Integrin activator kindlin-2 was recently found to associate with paxillin in nascent FAs, implicating an early yet undefined integrin outside-in signaling event. Here we show structurally that kindlin-2 recognizes paxillin via a distinct interface involving the ubiquitin-like kindlin-2 F0 domain and the paxillin LIM4 domain. The interface is adjacent to the membrane binding site of kindlin-2 F0, suggesting a mechanism for kindlin-2 to recruit paxillin to the membrane-proximal site where FA assembly is initiated. Disruption of the interface impaired the localization of paxillin, causing strong defects in FA assembly and cell migration. These data unveil a structural basis of the kindlin-2/paxillin interaction in controlling dynamic cell adhesion.

Keywords: FAK; focal adhesion; integrin; kindlin; nascent adhesion; paxillin; solution NMR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Binding Sites
  • Cell Adhesion*
  • Cell Movement
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism
  • Mice
  • Neoplasm Proteins / chemistry*
  • Neoplasm Proteins / metabolism
  • Paxillin / chemistry*
  • Paxillin / metabolism
  • Protein Binding

Substances

  • FERMT2 protein, human
  • Membrane Proteins
  • Neoplasm Proteins
  • Paxillin