3L8I

Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity

Summary for 3L8I

• Entry DOI: 10.2210/pdb3l8i/pdb
• Related: 3L8J
• Descriptor: Programmed cell death protein 10 (2 entities in total)
• Functional Keywords: cerebral cavernous malformation, fat domain, dimerization, protein binding
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q9BUL8
• Total number of polymer chains: 4
• Total formula weight: 99723.12

Authors

Li, X.,Zhang, R.,Zhang, H.,He, Y.,Ji, W.,Min, W.,Boggon, T.J. (deposition date: 2009-12-31, release date: 2010-05-19, Last modification date: 2024-02-21)

Primary citation

Li, X.,Zhang, R.,Zhang, H.,He, Y.,Ji, W.,Min, W.,Boggon, T.J.
Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity.
J.Biol.Chem., 285:24099-24107, 2010

PubMed Abstract: 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.

PubMed: 20489202
DOI: 10.1074/jbc.M110.128470

Experimental method

X-RAY DIFFRACTION (2.5 Å)