3rqe
From Proteopedia
Cerebral cavernous malformation 3 (CCM3) in complex with paxillin LD1
Structural highlights
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.[1] 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).[2] [3] [4] Publication Abstract from PubMedCerebral cavernous malformation (CCM) is a disease that affects between 0.1 and 0.5% of the human population, with mutations in CCM3 accounting for approximately 15% of the autosomal dominant form of the disease. We recently reported that CCM3 contains an N-terminal dimerization domain (CCM3D) and a C-terminal focal adhesion targeting (FAT)-homology domain. Intermolecular protein-protein interactions of CCM3 are mediated by a highly conserved surface on the FAT-homology domain and are affected by CCM3 truncations in the human disease. Here we report the crystal structures of CCM3 in complex with three different leucine-aspartate repeat (LD) motifs (LD1, LD2 and LD4) from the scaffolding protein paxillin, at 2.8 A, 2.7 A and 2.5 A resolution. We show that CCM3 binds LD motifs using the highly conserved Hydrophobic Patch 1 (HP1) and that this binding is similar to the binding of FAK and Pyk2 FAT domains to paxillin LD motifs. We further show by Surface Plasmon Resonance that CCM3 binds paxillin LD motifs with affinities in the micromolar range, similar to FAK family FAT domains. Finally, we show that endogenous CCM3 and paxillin co-localize in mouse cerebral pericytes. These studies provide a molecular-level framework to investigate the protein-protein interactions of CCM3. Molecular recognition of leucine-aspartate repeat (LD) motifs by the focal adhesion targeting-homology domain of cerebral cavernous malformation 3 (CCM3).,Li X, Ji W, Zhang R, Folta-Stogniew E, Min W, Boggon TJ J Biol Chem. 2011 Jun 1. PMID:21632544[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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