Format

Send to

Choose Destination
J Biol Chem. 2010 Jul 30;285(31):24099-107. doi: 10.1074/jbc.M110.128470. Epub 2010 May 19.

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

Author information

1
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.

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.

PMID:
20489202
PMCID:
PMC2911348
DOI:
10.1074/jbc.M110.128470
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center