4dx9

Publication Abstract from PubMed

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.

Mechanism for KRIT1 Release of ICAP1-Mediated Suppression of Integrin Activation.,Liu W, Draheim KM, Zhang R, Calderwood DA, Boggon TJ Mol Cell. 2013 Jan 9. pii: S1097-2765(12)01014-3. doi:, 10.1016/j.molcel.2012.12.005. PMID:23317506^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.