Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation.

Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined.