Structural basis for small G protein effector interaction of Ras-related protein 1 (Rap1) and adaptor protein Krev interaction trapped 1 (KRIT1).

Publication Type:

Journal Article


J Biol Chem, Volume 287, Issue 26, p.22317-27 (2012)


Amino Acid Sequence, Crystallography, X-Ray, Gene Expression Regulation, GTP Phosphohydrolases, Hemangioma, Cavernous, Central Nervous System, Humans, Integrins, KRIT1 Protein, Microtubule-Associated Proteins, Models, Biological, Models, Molecular, Molecular Sequence Data, Mutagenesis, Point Mutation, Protein Conformation, Protein Interaction Mapping, Protein Structure, Tertiary, Proto-Oncogene Proteins, rap1 GTP-Binding Proteins, Sequence Homology, Amino Acid, Signal Transduction


<p>Cerebral cavernous malformations (CCMs) 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 CCMs. 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 1.95 Å 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."</p>