4DXA

Co-crystal structure of Rap1 in complex with KRIT1

Summary for 4DXA

• Entry DOI: 10.2210/pdb4dxa/pdb
• Descriptor: Ras-related protein Rap-1b, Krev interaction trapped protein 1, 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE, ... (5 entities in total)
• Functional Keywords: gtpase, ferm, protein-protein interaction, gtp binding, cytoplasmic, protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane: P61224; Membrane; Peripheral membrane protein (Probable): O00522
• Total number of polymer chains: 2
• Total formula weight: 57142.55

Authors

Li, X.,Zhang, R.,Boggon, T.J. (deposition date: 2012-02-27, release date: 2012-05-16, Last modification date: 2023-09-13)

Primary citation

Li, X.,Zhang, R.,Draheim, K.M.,Liu, W.,Calderwood, D.A.,Boggon, T.J.
Structural Basis for Small G Protein Effector Interaction of Ras-related Protein 1 (Rap1) and Adaptor Protein Krev Interaction Trapped 1 (KRIT1).
J.Biol.Chem., 287:22317-22327, 2012

PubMed Abstract: 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."

PubMed: 22577140
DOI: 10.1074/jbc.M112.361295

Experimental method

X-RAY DIFFRACTION (1.95 Å)