Pellequer J L, Gale A J, Griffin J H, Getzoff E D
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
Blood Cells Mol Dis. 1998 Dec;24(4):448-61. doi: 10.1006/bcmd.1998.0214.
We present homology models of the C domains of coagulation factors V (FV) and VIII (FVIII). Using a threading approach, we identified the binding domain of galactose oxidase as an appropriate template for each C domain. The C1 and C2 domains of FV associate to form an elongated cylinder of 80A long and 30A diameter. The folding unit is a beta-sandwich with a long axis of 40A and a diameter of 30A. The current model allows us to propose a membrane binding mode for the C2 domains of FV and FVIII with three major characteristics: 1) solvent-exposed hydrophobic side chains from three loops at one end of the beta-sandwich are buried in the hydrophobic layer of the outer phospholipid leaflet; 2) a crown of positively charged residues is located in the polar zone of the phospholipid head groups; and 3) the long axis of the beta-sandwich of the C2 domain is perpendicular to the plane of the membrane. This proposal satisfies experimentally observed characteristics of membrane binding for the C2 domain and the light chain of FVa.
我们展示了凝血因子V（FV）和VIII（FVIII）C结构域的同源模型。通过穿线法，我们确定半乳糖氧化酶的结合结构域作为每个C结构域的合适模板。FV的C1和C2结构域结合形成一个长80埃、直径30埃的细长圆柱体。折叠单元是一个长轴为40埃、直径为30埃的β-折叠片层。当前模型使我们能够提出FV和FVIII的C2结构域的膜结合模式，其具有三个主要特征：1）β-折叠片层一端三个环上暴露于溶剂的疏水侧链埋入外层磷脂小叶的疏水层中；2）带正电荷残基的冠位于磷脂头部基团的极性区域；3）C2结构域β-折叠片层的长轴垂直于膜平面。该提议符合实验观察到的C2结构域和FVa轻链的膜结合特征。
