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The chemokine domain of fractalkine FKN-CD binds to the classical RGD-binding site of v 3 and that the resulting ternary complex formation integrin-FKN-CX3CR1 is critical for CX3CR1 signaling and FKN-induced integrin activation However only certain cell types express CX3CR1 Here we studied if FKN-CD can activate integrins in the absence of CX3CR1 We describe that WT FKN-CD activated recombinant soluble v 3 in cell-free conditions but the integrin-binding defective mutant of FKN-CD K36E R37E did not This suggests that FKN-CD can activate v 3 in the absence of CX3CR1 through the direct binding of FKN-CD to v 3 WT FKN-CD activated v 3 on CX3CR1-negative cells K562 and CHO but K36E R37E did not suggesting that FKN-CD can activate integrin at the cellular levels in a manner similar to that in cell-free conditions We hypothesized that FKN-CD enhances ligand binding to the classical RGD-binding site site 1 through binding to a second binding site site 2 that is distinct from site 1 in v 3 To identify the possible second FKN-CD binding site we performed docking simulation of v 3-FKN-CD interaction using v 3 with a closed inactive conformation as a target The simulation predicted a potential FKN-CD-binding site in inactive v 3 site 2 which is located at a crevice between v and 3 on the opposite side of site 1 in the v 3 headpiece We studied if FKN-CD really binds to site 2 using a peptide that is predicted to interact with FKN-CD in site 2 Notably the peptide specifically bound to FKN-CD and effectively suppressed integrin activation by FKN-CD This suggests that FKN-CD actually binds to site 2 and this leads to integrin activation We obtained very similar results in 4 1 and 5 1 The FKN binding to site 2 and resulting integrin activation may be a novel mechanism of integrin activation and of FKN signaling

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The chemokine fractalkine can activate integrins without CX3CR1 through direct binding to a ligand-binding site distinct...