Integrin αIIb tail distal of GFFKR participates in inside-out αIIbβ3 activation

A. Li, Q. Guo, C. Kim, W. Hu, F. Ye

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Increases in ligand binding to integrins (activation) play critical roles in platelet and leukocyte function. Integrin activation requires talin and kindlin binding to integrin β cytoplasmic tails. Research has focused on the conserved GFFKR motif in integrin αIIb tails, integrin β cytoplasmic tails and the binding partners of β tails. However, the roles of αIIb tail distal of GFFKR motif are unexplored. Objective: To investigate the role of αIIb tail distal of GFFKR in talin-mediated inside-out integrin signaling. Methods: We used model cell systems to examine the role of αIIb tail distal of GFFKR in bidirectional αIIbβ3 signaling and αIIbβ3-talin interactions. Results: Deletion of amino acid residues after the GFFKR motif in αIIb tail moderately decreased β3(D723R)-induced activation, abolished talin-induced αIIbβ3 activation in model cells, and inhibited agonist-induced αIIbβ3 activation in megakaryocytic cells. Furthermore, residues in αIIb tail distal of GFFKR did not affect outside-in αIIbβ3 signaling or αIIbβ3-talin interaction. Addition of non-homologous or non-specific amino acids to the GFFKR motif restored αIIbβ3 activation in model cells and in megakaryocytic cells. Molecular modeling indicates that β3-bound talin sterically clashes with the αIIb tail in the αIIbβ3 complexes, potentially disfavoring the α-β interactions that keep αIIbβ3 inactive. Conclusion: The αIIb tail sequences distal of GFFKR participate in talin-mediated inside-out αIIbβ3 activation through its steric clashes with β3-bound talin.

Original languageEnglish
Pages (from-to)1145-1155
Number of pages11
JournalJournal of Thrombosis and Haemostasis
Volume12
Issue number7
DOIs
Publication statusPublished - 2014 Jul

Keywords

  • Cell adhesion
  • Kindlin-2 protein, human
  • Signal transduction
  • Talin

ASJC Scopus subject areas

  • Hematology

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