| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
CCM3 mutations are associated with cerebral cavernous malformation (CCM), a disease affecting 0.1-0.5% of the human population. CCM3 (PDCD10, TFAR15) is thought to form a CCM complex with CCM1 and CCM2; however, the molecular basis for these interactions is not known. We have determined the 2.5 A crystal structure of CCM3. This structure shows an all alpha-helical protein containing two domains, an N-terminal dimerization domain with a fold not previously observed, and a C-terminal focal adhesion targeting (FAT)-homology domain. We show that CCM3 binds CCM2 via this FAT-homology domain and that mutation of a highly conserved FAK-like hydrophobic pocket (HP1) abrogates CCM3-CCM2 interaction. This CCM3 FAT-homology domain also interacts with paxillin LD motifs using the same surface, and partial CCM3 co-localization with paxillin in cells is lost on HP1 mutation. Disease-related CCM3 truncations affect the FAT-homology domain suggesting a role for the FAT-homology domain in the etiology of CCM.
Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity.,Li X, Zhang R, Zhang H, He Y, Ji W, Min W, Boggon TJ J Biol Chem. 2010 Jul 30;285(31):24099-107. Epub 2010 May 19. PMID:20489202[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bergametti F, Denier C, Labauge P, Arnoult M, Boetto S, Clanet M, Coubes P, Echenne B, Ibrahim R, Irthum B, Jacquet G, Lonjon M, Moreau JJ, Neau JP, Parker F, Tremoulet M, Tournier-Lasserve E. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet. 2005 Jan;76(1):42-51. Epub 2004 Nov 12. PMID:15543491 doi:10.1086/426952
- ↑ Bergametti F, Denier C, Labauge P, Arnoult M, Boetto S, Clanet M, Coubes P, Echenne B, Ibrahim R, Irthum B, Jacquet G, Lonjon M, Moreau JJ, Neau JP, Parker F, Tremoulet M, Tournier-Lasserve E. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet. 2005 Jan;76(1):42-51. Epub 2004 Nov 12. PMID:15543491 doi:10.1086/426952
- ↑ Ma X, Zhao H, Shan J, Long F, Chen Y, Chen Y, Zhang Y, Han X, Ma D. PDCD10 interacts with Ste20-related kinase MST4 to promote cell growth and transformation via modulation of the ERK pathway. Mol Biol Cell. 2007 Jun;18(6):1965-78. Epub 2007 Mar 14. PMID:17360971 doi:10.1091/mbc.E06-07-0608
- ↑ Fidalgo M, Fraile M, Pires A, Force T, Pombo C, Zalvide J. CCM3/PDCD10 stabilizes GCKIII proteins to promote Golgi assembly and cell orientation. J Cell Sci. 2010 Apr 15;123(Pt 8):1274-84. doi: 10.1242/jcs.061341. Epub 2010 Mar, 23. PMID:20332113 doi:10.1242/jcs.061341
- ↑ Li X, Zhang R, Zhang H, He Y, Ji W, Min W, Boggon TJ. Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity. J Biol Chem. 2010 Jul 30;285(31):24099-107. Epub 2010 May 19. PMID:20489202 doi:10.1074/jbc.M110.128470
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