Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity.
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.
Li
Xiaofeng
X
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Zhang
Rong
R
Zhang
Haifeng
H
He
Yun
Y
Ji
Weidong
W
Min
Wang
W
Boggon
Titus J
TJ
D051017:Apoptosis Regulatory Proteins / Q000737:chemistry*; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D018360:Crystallography, X-Ray / Q000379:methods; D019281:Dimerization; D020786:Hemangioma, Cavernous, Central Nervous System / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000737:chemistry*; D008968:Molecular Conformation; D009154:Mutation; D051419:Paxillin / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry*
D051017:Apoptosis Regulatory Proteins; D008565:Membrane Proteins; C495390:PDCD10 protein, human; D051419:Paxillin; D011518:Proto-Oncogene Proteins