Mechanism for KRIT1 release of ICAP1-mediated suppression of integrin activation.
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Liu W, Draheim KM, Zhang R, Calderwood DA, Boggon TJ
Mechanism for KRIT1 release of ICAP1-mediated suppression of integrin activation.
Mol Cell. 2013 Feb 21;49(4):719-29. doi: 10.1016/j.molcel.2012.12.005. Epub 2013 Jan 11.
- PubMed ID
- 23317506 [ View in PubMed]
- Abstract
KRIT1 (Krev/Rap1 Interaction Trapped-1) mutations are observed in approximately 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 beta1 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 beta1 cytoplasmic tail to 2.54 and 3.0 A resolution (the resolutions at which I/sigmaI = 2 are 2.75 and 3.0 A, respectively). We find that KRIT1 binds ICAP1 by a bidentate surface, that KRIT1 directly competes with integrin beta1 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.