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

Alexandre R. Gingras, Frederic Lagarrigue, Monica N. Cuevas, Andrew J. Valadez, Marcus Zorovich, Wilma McLaughlin, Miguel Alejandro Lopez-Ramirez, Nicolas Seban, Klaus Ley, William B. Kiosses, Mark H. Ginsberg

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1799-1809
Number of pages11
JournalJournal of Cell Biology
Issue number6
StatePublished - Jun 3 2019
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology


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