Staphylococci bind to the blood protein von Willebrand Factor (vWF), thereby causing endovascular infections. Whether and how this interaction occurs with the medically important pathogen Staphylococcus epidermidis is unknown. Using single-molecule experiments, we demonstrate that the S. epidermidis protein Aap binds vWF via an ultrastrong force, ∼3 nN, the strongest noncovalent biological bond ever reported, and we show that this interaction is activated by tensile loading, suggesting a catch-bond behavior. Aap-vWF binding involves exclusively the A1 domain of vWF but requires both the A and B domains of Aap, as revealed by inhibition assays using specific monoclonal antibodies. Collectively, our results point to a mechanism where force-induced unfolding of the B repeats activates the A domain of Aap, shifting it from a weak- to a strong-binding state, which then engages into an ultrastrong interaction with vWF A1. This shear-dependent function of Aap offers promise for innovative antistaphylococcal therapies.
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