Integrin ?II b tail distal of GFFKR participates in inside-out ?II b ?3 activation.

ABSTRACT: Increases in ligand binding to integrins (activation) play critical roles in platelet and leukocyte function. Integrin activation requires talin and kindlin binding to integrin ? cytoplasmic tails. Research has focused on the conserved GFFKR motif in integrin ?II b tails, integrin ? cytoplasmic tails and the binding partners of ? tails. However, the roles of ?II b tail distal of GFFKR motif are unexplored.To investigate the role of ?II b tail distal of GFFKR in talin-mediated inside-out integrin signaling.We used model cell systems to examine the role of ?II b tail distal of GFFKR in bidirectional ?II b ?3 signaling and ?II b ?3 -talin interactions.Deletion of amino acid residues after the GFFKR motif in ?II b tail moderately decreased ?3 (D723R)-induced activation, abolished talin-induced ?II b ?3 activation in model cells, and inhibited agonist-induced ?II b ?3 activation in megakaryocytic cells. Furthermore, residues in ?II b tail distal of GFFKR did not affect outside-in ?II b ?3 signaling or ?II b ?3 -talin interaction. Addition of non-homologous or non-specific amino acids to the GFFKR motif restored ?II b ?3 activation in model cells and in megakaryocytic cells. Molecular modeling indicates that ?3 -bound talin sterically clashes with the ?II b tail in the ?II b ?3 complexes, potentially disfavoring the ?-? interactions that keep ?II b ?3 inactive.The ?II b tail sequences distal of GFFKR participate in talin-mediated inside-out ?II b ?3 activation through its steric clashes with ?3 -bound talin.

SUBMITTER: Li A 

PROVIDER: S-EPMC4107134 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature