A novel functional role for the highly conserved α-subunit KVGFFKR motif distinct from integrin αIIbβ3 activation processes

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The highly conserved integrin α-subunit membrane-proximal motif KVGFFKR plays a decisive role in modulating the activation of integrin αIIbβ3. Previously, we have shown that a platelet permeable palmityl (pal)-peptide with this seven amino acid sequence can directly activate αIIbβ3 leading to platelet aggregation.


To investigate further the role of the KVGFFKR motif in integrin αIIbβ3 function.


We used two sequence-specific complementary model systems, palmityl pal-peptides in platelets, and mutant αIIbβ3-expressing Chinese Hamster Ovary (CHO) cell lines.


In platelets we show that the two phenylalanine amino acids in pal-KVGFFKR (pal-FF) peptide are critical for stimulating platelet aggregation. Pal-FF peptide treatment of platelets also gives rise to a tyrosine phosphorylation signal despite the presence of inhibitors of fibrinogen binding. In CHO cells, a double alanine substitution, αIIb(F992A, F993A)β3, induces constitutive integrin activation but prevents actin stress fiber formation upon adhesion to fibrinogen, suggesting that αIIbβ3-mediated cytoskeletal reorganization is also dependent on F992 and F993. This further highlights a critical role for the two phenylalanine residues in both of these αIIbβ3-mediated processes.


In addition to regulating integrin αIIbβ3 activation state, the KVGFFKR motif also influences cytoskeletal reorganization. This activity is critically determined by F992 and F993 within the seven amino acid sequence.

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