4wj7

CCM2 PTB domain in complex with KRIT1 NPxY/F3

spinqualitylabelsall models 4wj7, resolution 2.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4wj7 is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.753Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CCM2_HUMAN Hereditary cerebral cavernous malformation. The disease is caused by mutations affecting the gene represented in this entry. Function CCM2_HUMAN Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity. May act through the stabilization of endothelial cell junctions (By similarity). May function as a scaffold protein for MAP2K3-MAP3K3 signaling. Seems to play a major role in the modulation of MAP3K3-dependent p38 activation induced by hyperosmotic shock (By similarity). Publication Abstract from PubMed Familial cerebral cavernous malformations (CCMs) are predominantly neurovascular lesions and are associated with mutations within the KRIT1, CCM2, and PDCD10 genes. The protein products of KRIT1 and CCM2 (Krev interaction trapped 1 (KRIT1) and cerebral cavernous malformations 2 (CCM2), respectively) directly interact with each other. Disease-associated mutations in KRIT1 and CCM2 mostly result in loss of their protein products, although rare missense point mutations can also occur. From gene sequencing of patients known or suspected to have one or more CCMs, we discover a series of missense point mutations in KRIT1 and CCM2 that result in missense mutations in the CCM2 and KRIT1 proteins. To place these mutations in the context of the molecular level interactions of CCM2 and KRIT1, we map the interaction of KRIT1 and CCM2 and find that the CCM2 phosphotyrosine binding (PTB) domain displays a preference towards the third of the three KRIT1 NPxY/F motifs. We determine the 2.75 A co-crystal structure of the CCM2 PTB domain with a peptide corresponding to KRIT1NPxY/F3, revealing a Dab-like PTB fold for CCM2 and its interaction with KRIT1NPxY/F3. We find that several disease-associated missense mutations in CCM2 have the potential to interrupt the KRIT1:CCM2 interaction by destabilizing the CCM2 PTB domain, and that a KRIT1 mutation also disrupts this interaction. We therefore provide new insights into the architecture of CCM2 and how the CCM complex is disrupted in CCM disease. Structural basis for the disruption of the Cerebral Cavernous Malformations 2 (CCM2) interaction with Krev Interaction Trapped 1 (KRIT1) by disease-associated mutations.,Fisher OS, Liu W, Zhang R, Stiegler AL, Ghedia S, Weber JL, Boggon TJ J Biol Chem. 2014 Dec 18. pii: jbc.M114.616433. PMID:25525273 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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