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The ability of adhesion receptors to transmit biochemical signals and mechanical force across cell membranes depends on interactions with the actin cytoskeleton. Human filamins are large actin cross-linking proteins that connect integrins to the cytoskeleton. Filamin binding to the cytoplasmic tail of beta integrins has been shown to prevent integrin activation in cells, which is important for controlling cell adhesion and migration. The molecular level mechanism for filamin binding to integrin has, however, been unclear, as recently, it was been demonstrated, that filamin undergoes intramolecular auto-inhibition of integrin binding. Here, using steered molecular dynamics simulations, we show that mechanical force applied to filamin can expose the cryptic integrin binding sites. The forces required for this are considerably lower than those for filamin immunoglobulin domain unfolding. The mechanical force induced unfolding of filamin and exposure of integrin binding sites occurs through stable intermediates, where the integrin binding is possible. Accordingly, our results support filamin's role as mechanotransducer, since force induced conformational changes allow binding of integrin and also other transmembrane and intracellular proteins. This observed force-induced conformational change can also be one of possible mechanisms involved in the regulation of integrin activation.
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