Mechanism for KRIT1 Release of ICAP1-Mediated Suppression of Integrin Activation

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KRIT1 (Krev/Rap1 Interaction Trapped-1) mutations are observed in ~40% of autosomal-dominant cerebral cavernous malformations (CCMs), a disease occurring in up to 0.5% of the population. We show that KRIT1 functions as a switch for β1 integrin activation by antagonizing ICAP1 (Integrin Cytoplasmic Associated Protein-1)-mediated modulation of " inside-out" activation. We present cocrystal structures of KRIT1 with ICAP1 and ICAP1 with integrin β1 cytoplasmic tail to 2.54 and 3.0 å resolution (the resolutions at which I/σ. I = 2 are 2.75 and 3.0 å, respectively). We find that KRIT1 binds ICAP1 by a bidentate surface, that KRIT1 directly competes with integrin β1 to bind ICAP1, and that KRIT1 antagonizes ICAP1-modulated integrin activation using this site. We also find that KRIT1 contains an N-terminal Nudix domain, in a region previously designated as unstructured. We therefore provide insights to integrin regulation and CCM-associated KRIT1 function. © 2013 Elsevier Inc..




Liu, W., Draheim, K. M., Zhang, R., Calderwood, D. A., & Boggon, T. J. (2013). Mechanism for KRIT1 Release of ICAP1-Mediated Suppression of Integrin Activation. Molecular Cell, 49(4), 719–729.

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