Structural studies of cerebral cavernous malformations 2 (CCM2) reveal a folded helical domain at its C-terminus

• Published in: FEBS letters Vol. 587; no. 3; pp. 272 - 277
• Main Authors: Fisher, Oriana S., Zhang, Rong, Li, Xiaofeng, Murphy, James W., Demeler, Borries, Boggon, Titus J.
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 31-01-2013
• Subjects: Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - metabolism; Amino Acid Sequence; Binding Sites; Cadherins - metabolism; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Cerebral cavernous malformation; Crystallography, X-Ray; Harmonin-homology domain; Humans; Models, Molecular; Molecular Sequence Data; Protein Folding; Protein Multimerization; Protein Structure, Secondary; Protein Structure, Tertiary; Protein–protein interaction; Sequence Homology, Amino Acid; Signal transduction; X-ray crystallography; X-ray crystallography; Signal transduction; Cerebral cavernous malformation; Harmonin-homology domain; Protein–protein interaction
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2012.12.011

► Limited proteolysis reveals a C-terminal domain in CCM2. ► The 1.9Å crystal structure of the CCM2 C-terminal domain is determined. ► CCM2 C-terminal domain is structurally homologous to harmonin. ► We term this domain the CCM2 harmonin-homology domain, HHD. ► This domain may represent a regulated site of protein–protein interaction for CCM2.
Cerebral cavernous malformations (CCM) are neurovascular dysplasias affecting up to 0.5% of the population. Mutations in the CCM2 gene are associated with acquisition of CCM. We identify a previously uncharacterized domain at the C-terminus of CCM2 and determine its 1.9Å resolution crystal structure. Because this domain is structurally homologous to the N-terminal domain of harmonin, we name it the CCM2 harmonin-homology domain or HHD. CCM2 HHD is observed in two conformations, and we employ analytical ultracentrifugation to test its oligomerization. Additionally, CCM2 HHD contains an unusually long 13-residue 310 helix. This study provides the first structural characterization of CCM2.
CCM2binds to CCM3 by pull down (View interaction)
CCM2 and CCM2bind by X-ray crystallography (View interaction)
CCM2 and CCM2bind by molecular sieving (View interaction)