4dxa

Publication Abstract from PubMed

Cerebral cavernous malformations (CCM) affect 0.1-0.5% of the population resulting in leaky vasculature and severe neurological defects. KRIT1 (Krev interaction trapped-1) mutations associate with ~40% of familial CCM. KRIT1 is an effector of Ras-related protein 1 (Rap1) GTPase. Rap1 relocalizes KRIT1 from microtubules to cell membranes to impact integrin activation, potentially important for CCM pathology. We report the 1.95A co-crystal structure of KRIT1 FERM domain in complex with Rap1. Rap1-KRIT1 interaction encompasses an extended surface, including Rap1 Switch I and II and KRIT1 FERM F1 and F2 lobes. Rap1 binds KRIT1-F1 lobe using a GTPase-ubiquitin-like fold interaction, but binds KRIT1-F2 lobe by a novel interaction. Point mutagenesis confirms the interaction. High similarity between KRIT1-F2/F3 and Talin is revealed. Additionally, the mechanism for FERM domains acting as GTPase effectors is suggested. Finally, structure-based alignment of each lobe suggests classification of FERM domains as ERM-like and TMFK-like (Talin-Myosin-FAK-Krit-like) and that FERM lobes resemble domain modules.

Structural basis for the small G-protein-effector interaction of Ras-related protein 1 (Rap1) and the adaptor protein Krev interaction trapped 1 (KRIT1).,Li X, Zhang R, Draheim KM, Liu W, Calderwood DA, Boggon TJ J Biol Chem. 2012 May 10. PMID:22577140^[3]

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