Structure of Rap1b Bound to Talin Reveals a Pathway for Triggering Integrin Activation

Nat Commun. 2017 Nov 23;8(1):1744. doi: 10.1038/s41467-017-01822-8.

Abstract

Activation of transmembrane receptor integrin by talin is essential for inducing cell adhesion. However, the pathway that recruits talin to the membrane, which critically controls talin's action, remains elusive. Membrane-anchored mammalian small GTPase Rap1 is known to bind talin-F0 domain but the binding was shown to be weak and thus hardly studied. Here we show structurally that talin-F0 binds to human Rap1b like canonical Rap1 effectors despite little sequence homology, and disruption of the binding strongly impairs integrin activation, cell adhesion, and cell spreading. Furthermore, while being weak in conventional binary binding conditions, the Rap1b/talin interaction becomes strong upon attachment of activated Rap1b to vesicular membranes that mimic the agonist-induced microenvironment. These data identify a crucial Rap1-mediated membrane-targeting mechanism for talin to activate integrin. They further broadly caution the analyses of weak protein-protein interactions that may be pivotal for function but neglected in the absence of specific cellular microenvironments.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Adhesion / physiology
  • Cell Line
  • Cell Membrane / metabolism
  • Guanosine Triphosphate / metabolism
  • Humans
  • Integrins / metabolism*
  • Mice
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Talin / chemistry*
  • Talin / genetics
  • Talin / metabolism*
  • rap GTP-Binding Proteins / chemistry*
  • rap GTP-Binding Proteins / metabolism*

Substances

  • Integrins
  • Recombinant Proteins
  • Talin
  • talin protein, mouse
  • Guanosine Triphosphate
  • RAP1B protein, human
  • rap GTP-Binding Proteins