4tvq

CCM3 in complex with CCM2 LD-like motif

spinqualitylabelsall models 4tvq, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4tvq is a 5 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 2.8Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PDC10_HUMAN Hereditary cerebral cavernous malformation. Defects in PDCD10 are the cause of cerebral cavernous malformations type 3 (CCM3) [MIM:603285. Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. CCMs have an incidence of 0.1%-0.5% in the general population and usually present clinically during the 3rd to 5th decade of life. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. Function PDC10_HUMAN Promotes cell proliferation. Modulates apoptotic pathways. Increases mitogen-activated protein kinase activity and MST4 activity. Important for cell migration, and for normal structure and assembly of the Golgi complex. Important for KDR/VEGFR2 signaling. Increases the stability of KDR/VEGFR2 and prevents its breakdown. Required for normal cardiovascular development. Required for normal angiogenesis, vasculogenesis and hematopoiesis during embryonic development (By similarity). Publication Abstract from PubMed Mutations in the essential adaptor proteins CCM2 or CCM3 lead to cerebral cavernous malformations (CCM), vascular lesions that most frequently occur in the brain and are strongly associated with hemorrhagic stroke, seizures, and other neurological disorders. CCM2 binds CCM3, but the molecular basis of this interaction, and its functional significance, have not been elucidated. Here, we used x-ray crystallography and structure-guided mutagenesis to show that an alpha-helical LD-like motif within CCM2 binds the highly conserved "HP1" pocket of the CCM3 focal adhesion targeting (FAT) homology domain. By knocking down CCM2 or CCM3 and rescuing with binding-deficient mutants, we establish that CCM2-CCM3 interactions protect CCM2 and CCM3 proteins from proteasomal degradation and show that both CCM2 and CCM3 are required for normal endothelial cell network formation. However, CCM3 expression in the absence of CCM2 is sufficient to support normal cell growth, revealing complex-independent roles for CCM3. CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation.,Draheim KM, Li X, Zhang R, Fisher OS, Villari G, Boggon TJ, Calderwood DA J Cell Biol. 2015 Mar 30;208(7):987-1001. doi: 10.1083/jcb.201407129. PMID:25825518 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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