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

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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.


To investigate the role of αIIb tail distal of GFFKR in talin-mediated inside-out integrin signaling.


We used model cell systems to examine the role of αIIb tail distal of GFFKR in bidirectional αIIbβ3 signaling and αIIbβ3–talin interactions.


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.


The αIIb tail sequences distal of GFFKR participate in talin-mediated inside-out αIIbβ3 activation through its steric clashes with β3-bound talin.

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