Rap1 binding and a lipid-dependent helix in talin F1 domain promote integrin activation in tandem

Rap1 GTPases bind effectors, such as RIAM, to enable talin1 to induce integrin activation. In addition, Rap1 binds directly to the talin1 F0 domain (F0); however, this interaction makes a limited contribution to integrin activation in CHO cells or platelets. Here, we show that talin1 F1 domain (F1) contains a previously undetected Rap1-binding site of similar affinity to that in F0. A structure-guided point mutant (R118E) in F1, which blocks Rap1 binding, abolishes the capacity of Rap1 to potentiate talin1-induced integrin activation. The capacity of F1 to mediate Rap1-dependent integrin activation depends on a unique loop in F1 that has a propensity to form a helix upon binding to membrane lipids. Basic membrane-facing residues of this helix are critical, as charge-reversal mutations led to dramatic suppression of talin1-dependent activation. Thus, a novel Rap1-binding site and a transient lipid-dependent helix in F1 work in tandem to enable a direct Rap1–talin1 interaction to cause integrin activation.

Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Gingras, A. R., Lagarrigue, F., Cuevas, M. N., Valadez, A. J., Zorovich, M., McLaughlin, W., Lopez-Ramirez, M. A., Seban, N., Ley, K., Kiosses, W. B., Ginsberg, M. H. Tags: Adhesion, Cell Signaling, Biochemistry Reports Source Type: research