Nan Ruodan, Furze Christopher M, Wright David W, Gor Jayesh, Wallis Russell, Perkins Stephen J
Department of Structural and Molecular Biology, Division of Biosciences, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
Departments of Infection, Immunity and Inflammation and Molecular Cell Biology, University of Leicester, University Road, Leicester, LE1 9HN, UK.
Structure. 2017 Feb 7;25(2):364-375. doi: 10.1016/j.str.2016.12.014. Epub 2017 Jan 19.
The lectin pathway of complement is activated by complexes comprising a recognition component (mannose-binding lectin, serum ficolins, collectin-LK or collectin-K1) and a serine protease (MASP-1 or MASP-2). MASP-1 activates MASP-2, and MASP-2 cleaves C4 and C4b-bound C2. To clarify activation, new crystal structures of Ca-bound MASP dimers were determined, together with their solution structures from X-ray scattering, analytical ultracentrifugation, and atomistic modeling. Solution structures of the CUB1-EGF-CUB2 dimer of each MASP indicate that the two CUB2 domains were tilted by as much as 90° compared with the crystal structures, indicating considerable flexibility at the EGF-CUB2 junction. Solution structures of the full-length MASP dimers in their zymogen and activated forms revealed similar structures that were much more bent than anticipated from crystal structures. We conclude that MASP-1 and MASP-2 are flexible at multiple sites and that this flexibility may permit both intra- and inter-complex activation.
补体的凝集素途径由包含识别成分（甘露糖结合凝集素、血清纤维胶凝蛋白、凝集素-LK或凝集素-K1）和丝氨酸蛋白酶（MASP-1或MASP-2）的复合物激活。MASP-1激活MASP-2，而MASP-2裂解C4和与C4b结合的C2。为阐明激活机制，测定了结合钙的MASP二聚体的新晶体结构，以及通过X射线散射、分析型超速离心和原子模型得到的其溶液结构。每个MASP的CUB1-EGF-CUB2二聚体的溶液结构表明，与晶体结构相比，两个CUB2结构域倾斜多达90°，表明EGF-CUB2连接处具有相当大的灵活性。全长MASP二聚体的酶原形式和激活形式的溶液结构显示出相似的结构，其弯曲程度比晶体结构预期的要大得多。我们得出结论，MASP-1和MASP-2在多个位点具有灵活性，这种灵活性可能允许复合物内部和复合物之间的激活。
