Poster Presentation 2014 International Biophysics Congress

Crystal structures and function research of cerebral cavernous malformations 2 C-domain and its complex with mitogen-activated protein kinase /extracellular signal-regulated kinase kinase kinase 3 (#565)

Xiaoyan Wang 1 , Kai Deng 2
  1. Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, China
  2. Institute of Eugenics and Genetics, Renmin Hospital, Hubei University of Medicine, Shiyan, China
Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the CNS, which can result in a variety of neurological disabilities, including hemorrhagic stroke and seizures. To date, there is not any known homologous structure of CCM2 reported. CCM2 contains two independent domains. The N-terminus of CCM2 is a phosphotyrosine binding (PTB) domain, and the C-terminus of CCM2 is called the Karet domains, which is required for death signaling. Here we report the crystal structures of CCM2(MGC4607, OSM) C-domain, CCM2 -Ct(residues 290-444) at 2.7Å.  The overall structure of CCM2-Ct consists of six helices (α1-α6), all the six helices fold into a compact six-helix bundle, in which the tandem α1-α5 helices make up the major fragment and the sole α6 constitutes the minor fragment. A number of hydrophobic residues in the four helices, form a hydrophobic core to stabilize the structure. On the outside surface of each helix-hairpin, there is a preformed cleft. The last two helices, α5 and α6, are wedged into the clefts. The long flexible loop (residues 378-423) linking the sole helix and the α1-α5 degrades spontaneously. On the basis of the structure’s feature, we align the C-domain to other protein complex in the PDB. We put up this hypothesis that CCM2 could bind to its target proteins by exchanging the helix as an important adaptor protein.