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首页> 外文期刊>Journal of Molecular Biology >The extended multidomain solution structures of the complement protein crry and its chimeric conjugate crry-Ig by scattering, analytical ultracentrifugation and constrained modelling: implications for function and therapy.
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The extended multidomain solution structures of the complement protein crry and its chimeric conjugate crry-Ig by scattering, analytical ultracentrifugation and constrained modelling: implications for function and therapy.

机译：补体蛋白crry及其嵌合共轭物crry-Ig的扩展多域溶液结构，通过散射，分析超速离心和约束建模：对功能和治疗的意义。

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Complement receptor-related gene/protein y (Crry) is a cell membrane-bound regulator of complement activation found in mouse and rat. Crry contains only short complement/consensus repeat (SCR) domains. X-ray and neutron scattering was performed on recombinant rat Crry containing the first five SCR domains (rCrry) and mouse Crry with five SCR domains conjugated to the Fc fragment of mouse IgG1 (mCrry-Ig) in order to determine their solution structures at medium resolution. The radius of gyration R(G) of rCrry was determined to be 4.9-5.0 nm, and the R(G) of the cross-section was 1.2-1.5 nm as determined by X-ray and neutron scattering. The R(G) of mCrry-Ig was 6.6-6.7 nm, and the R(G) of the cross-section were 2.3-2.4 nm and 1.3 nm. The maximum dimension of rCrry was 18 nm and that for mCrry-Ig was 26 nm. The neutron data indicated that rCrry and mCrry-Ig have molecular mass values of 45,000Da and 140,000Da, respectively, in agreement with their sequences, and sedimentation equilibrium data supported these determinations. Time-derivative velocity experiments gave sedimentation coefficients of 2.4S for rCrry and 5.4S for mCrry-Ig. A medium-resolution model of rCrry was determined using homology models that were constructed for the first five SCR domains of Crry from known crystal and NMR structures, and linked by randomly generated linker peptide conformations. These trial-and-error calculations revealed a small family of extended rCrry structures that best accounted for the scattering and ultracentrifugation data. These were shorter than the most extended rCrry models as the result of minor bends in the inter-SCR orientations. The mCrry-Ig solution data were modelled starting from a fixed structure for rCrry and the crystal structure of mouse IgG1, and was based on conformational searches of the hinge peptide joining the mCrry and Fc fragments. The best-fit models showed that the two mCrry antennae in mCrry-Ig were extended from the Fc fragment. No preferred orientation of the antennae was identified, andthis indicated that the accessibility of the antennae for the molecular targets C4b and C3b was not affected by the covalent link to Fc. A structural comparison between Crry and complement receptor type 1 indicated that the domain arrangement of Crry SCR 1-3 is as extended as that of the CR1 SCR 15-17 NMR structure.
机译：补体受体相关基因/蛋白质y（Crry）是在小鼠和大鼠中发现的细胞膜结合的补体激活调节剂。 Crry仅包含短的补体/共有重复（SCR）域。对含有大鼠前五个SCR结构域（rCrry）和具有五个SCR域与小鼠IgG1 Fc片段（mCrry-Ig）共轭的小鼠Crry的重组大鼠Crry进行X射线和中子散射，以确定它们在培养基中的溶液结构解析度。通过X射线和中子散射测定，rCrry的回转半径R（G）为4.9〜5.0nm，截面的R（G）为1.2〜1.5nm。 mCrry-Ig的R（G）为6.6-6.7nm，并且截面的R（G）为2.3-2.4nm和1.3nm。 rCrry的最大尺寸为18 nm，mCrry-Ig的最大尺寸为26 nm。中子数据表明，rCrry和mCrry-Ig的分子质量值与其序列相符，分别为45,000Da和140,000Da，沉降平衡数据支持了这些测定。时间微分速度实验给出的沉降系数为rCrry为2.4S，mCrry-Ig为5.4S。使用同源性模型确定了rCrry的中等分辨率模型，该同源性模型是根据已知的晶体和NMR结构为Crry的前五个SCR结构域构建的，并通过随机生成的接头肽构象进行链接。这些反复试验的计算揭示了一小部分扩展的rCrry结构，这些结构最能说明散射和超速离心数据。由于SCR方向之间的弯曲较小，因此比最扩展的rCrry模型要短。 mCrry-Ig溶液数据从rCrry的固定结构和小鼠IgG1的晶体结构开始建模，并且基于连接mCrry和Fc片段的铰链肽的构象搜索。最佳拟合模型显示，mCrry-Ig中的两个mCrry触角从Fc片段延伸。没有确定触角的优选取向，这表明触角对分子靶标C4b和C3b的可及性不受与Fc的共价连接的影响。 Crry和1型补体受体之间的结构比较表明，Crry SCR 1-3的域排列与CR1 SCR 15-17 NMR结构的域排列一样扩展。

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