Intrinsically disordered region of talin’s FERM domain functions as an initial PIP2 recognition site [research data]

Focal adhesions (FAs) mediate the interaction of the cytoskeleton with the extracellular matrix (ECM) in a highly dynamic fashion. talin is a central regulator, adaptor protein and mechano-sensor of focal adhesion complexes. For recruitment and firm attachment at FAs, talin’s N-terminal FERM domain binds to phosphatidylinositol 4,5-bisphosphate (PIP<sub>2</sub>)-enriched membranes. A newly published autoinhibitory structure of talin-1, where the known PIP<sub>2</sub> interaction sites are covered up, lead us to hypothesize that a hitherto less examined loop insertion of the FERM domain acts as an additional and initial site of contact. We evaluated direct interactions of talin-1 with a PIP<sub>2</sub> membrane by means of atomistic molecular dynamics (MD) simulations. We show that this unstructured, 33-residue-long loop strongly interacts with PIP<sub>2</sub> and can facilitate further membrane contacts, including the canonical PIP<sub>2</sub> interactions, by serving as a flexible membrane anchor. Under force as present at FAs, the extensible FERM loop ensures talin to maintain membrane contacts when pulled away from the membrane by up to 7 nm. We identify key basic residues of the anchor mediating the highly dynamic talin-membrane interaction. Our results put forward an intrinsically disordered loop as a key and highly adaptable PIP<sub>2</sub> recognition site of talin and potentially other PIP<sub>2</sub>-binding mechano-proteins.
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This dataset contains setup scripts, molecular dynamics parameters, input files and derived data from the molecular dynamics simulations of this paper available at <a href="https://graeter-group.github.io/paper-talin-loop/">https://graeter-group.github.io/paper-talin-loop/</a> or <a href="https://doi.org/10.1016/j.bpj.2023.02.020">https://doi.org/10.1016/j.bpj.2023.02.020</a>.