4y5o

CCM2 HHD in complex with MEKK3 NPB1

spinqualitylabelsall models 4y5o, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4y5o is a 2 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 2.35Å 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 Cerebral cavernous malformations 2 (CCM2) loss is associated with the familial form of CCM disease. The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis in mice and interacts physically with CCM2, but how this interaction is mediated and its relevance to cerebral vasculature are unknown. Here we report that Mekk3 plays an intrinsic role in embryonic vascular development. Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain blood vessels leakage. We discover direct interaction between CCM2 harmonin homology domain (HHD) and the N terminus of MEKK3, and determine a 2.35 A cocrystal structure. We find Mekk3 deficiency impairs neurovascular integrity, which is partially dependent on Rho-ROCK signalling, and that disruption of MEKK3:CCM2 interaction leads to similar neurovascular leakage. We conclude that CCM2:MEKK3-mediated regulation of Rho signalling is required for maintenance of neurovascular integrity, unravelling a mechanism by which CCM2 loss leads to disease. Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex.,Fisher OS, Deng H, Liu D, Zhang Y, Wei R, Deng Y, Zhang F, Louvi A, Turk BE, Boggon TJ, Su B Nat Commun. 2015 Aug 3;6:7937. doi: 10.1038/ncomms8937. PMID:26235885 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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