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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Solution structure of the A4 domain of factor XI sheds light on the mechanism of zymogen activation
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Solution structure of the A4 domain of factor XI sheds light on the mechanism of zymogen activation

机译：XI因子A4结构域的溶液结构阐明了酶原激活的机制

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摘要

Factor XI (FXI) is a homodimeric blood coagulation protein. Each monomer comprises four tandem apple-domain repeats (A1-A4) and a serine protease domain. We report here the NMR solution structure of the A4 domain (residues 272-361), which mediates formation of the disulfide-linked FXI dimer. A4 exhibits characteristic features of the plasminogen apple nematode domain family, including a five-stranded β-sheet flanked by an α-helix on one side and a two-stranded β-sheet on the other. In addition, the solution structure reveals a second α-helix at the C terminus. Comparison with a recent crystal structure of full-length FXI, combined with molecular modeling, suggests that the C-terminal helix is formed only upon proteolytic activation. The newly formed helix disrupts interdomain contacts and reorients the catalytic domains, bringing the active sites into close proximity. This hypothesis is supported by small-angle x-ray scattering and electron microscopy data, which indicate that FXI activation is accompanied by a major change in shape. The results are consistent with biochemical evidence that activated FXI cleaves its substrate at two positions without release of an intermediate.
机译：因子XI（FXI）是一种同型二聚体凝血蛋白。每个单体包含四个串联的苹果结构域重复序列（A1-A4）和一个丝氨酸蛋白酶结构域。我们在这里报告了A4域的NMR溶液结构（残基272-361），该结构介导了二硫键连接的FXI二聚体的形成。 A4表现出纤溶酶原苹果线虫域家族的特征，包括一侧为α-螺旋的五链β-折叠，另一侧为二链β-折叠。此外，溶液结构在C末端显示出第二个α-螺旋。与全长FXI的最新晶体结构的比较，结合分子建模，表明C末端螺旋仅在蛋白水解激活后形成。新形成的螺旋结构破坏了区域间的接触并重新排列了催化区域，使活性位点紧密接近。这个假设得到小角度X射线散射和电子显微镜数据的支持，这些数据表明FXI激活伴随着形状的重大变化。结果与生物化学证据一致，即活化的FXI在两个位置裂解其底物而没有释放中间体。

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