Insights Into Enhanced Complement Activation by Structures of Properdin and Its Complex With the C-Terminal Domain of C3b
Insights Into Enhanced Complement Activation by Structures of Properdin and Its Complex With the C-Terminal Domain of C3b
复制标题
深入了解备解素及其与 C3b C 末端结构域的复合物的结构增强补体激活
DOI：
10.3389/fimmu.2019.02097
复制
发表时间：
2019
影响因子：
7.3
通讯作者：
P. Gros
中科院分区：
文献类型：
--
作者：
R. M. van den Bos;N. Pearce;J. Granneman;T. Brondijk;P. Gros
备解素增强补体介导的靶细胞和颗粒的调理作用以用于免疫清除。备解素在人血浆中以二聚体、三聚体和四聚体形式存在，其识别C3 b沉积表面，促进形成，并延长将C3转化为C3 b的C3 bBb-酶复合物的寿命，从而增强补体扩增环。在这里，我们报告的晶体结构的单体化备解素，这是由单独的N-和C-末端结构，产生单体大小的备解素复合物，稳定C3 bBb的共表达。与先前的低分辨率X射线和EM数据一致，晶体结构揭示了由一个原聚体的血小板反应蛋白I型重复序列（TSR）结构域4和6分别与第二个原聚体的N-末端结构域（采用短的转化生长因子B结合蛋白样折叠）和结构域TSR 1相互作用形成的环形排列。接下来，与C3 b的C-末端结构域复合的单体化备解素的结构显示备解素结构域TSR 5沿着C3 b的C-末端α-螺旋结合，而两个环，一个来自结构域TSR 5，一个来自TSR 6，像马镫一样围绕C3 b C-末端延伸和折叠。这表明了一种机制模型，其中这些TSR 5和TSR 6“马镫”桥接C3 B和因子B或其片段B B之间的相互作用，从而增强C3 b B前转化酶的形成并稳定C3 b B B转化酶。此外，备解素TSR 6将在空间上阻断蛋白酶因子I与C3 b的结合，从而限制C3 b蛋白水解降解。在TSR 4中TSR结构域的典型Trp-梯中存在缬氨酸而不是第三个色氨酸允许显著的ca. TSR 4的60°畴弯曲运动。连同TSR 2的可变定位和，pupirin，TSR 3，这解释了备解素形成二聚体，三聚体和四聚体所需的构象灵活性。总之，结果表明，需要寡聚备解素的结合亲合力来区分表面沉积的C3 b分子与可溶性C3 b或C3，并表明备解素介导的桥接C3 b-B和C3 b-Bb的相互作用增强亲和力，从而促进转化酶的形成和稳定。这些机制解释了补体介导的靶细胞和颗粒的调理作用的增强，用于免疫清除。
Properdin enhances complement-mediated opsonization of targeted cells and particles for immune clearance. Properdin occurs as dimers, trimers and tetramers in human plasma, which recognize C3b-deposited surfaces, promote formation, and prolong the lifetime of C3bBb-enzyme complexes that convert C3 into C3b, thereby enhancing the complement-amplification loop. Here, we report crystal structures of monomerized properdin, which was produced by co-expression of separate N- and C-terminal constructs that yielded monomer-sized properdin complexes that stabilized C3bBb. Consistent with previous low-resolution X-ray and EM data, the crystal structures revealed ring-shaped arrangements that are formed by interactions between thrombospondin type-I repeat (TSR) domains 4 and 6 of one protomer interacting with the N-terminal domain (which adopts a short transforming-growth factor B binding protein-like fold) and domain TSR1 of a second protomer, respectively. Next, a structure of monomerized properdin in complex with the C-terminal domain of C3b showed that properdin-domain TSR5 binds along the C-terminal α-helix of C3b, while two loops, one from domain TSR5 and one from TSR6, extend and fold around the C3b C-terminus like stirrups. This suggests a mechanistic model in which these TSR5 and TSR6 “stirrups” bridge interactions between C3b and factor B or its fragment Bb, and thereby enhance formation of C3bB pro-convertases and stabilize C3bBb convertases. In addition, properdin TSR6 would sterically block binding of the protease factor I to C3b, thus limiting C3b proteolytic degradation. The presence of a valine instead of a third tryptophan in the canonical Trp-ladder of TSR domains in TSR4 allows a remarkable ca. 60°-domain bending motion of TSR4. Together with variable positioning of TSR2 and, putatively, TSR3, this explains the conformational flexibility required for properdin to form dimers, trimers, and tetramers. In conclusion, the results indicate that binding avidity of oligomeric properdin is needed to distinguish surface-deposited C3b molecules from soluble C3b or C3 and suggest that properdin-mediated interactions bridging C3b-B and C3b-Bb enhance affinity, thus promoting convertase formation and stabilization. These mechanisms explain the enhancement of complement-mediated opsonization of targeted cells and particle for immune clearance.
登录
查看更多内容
pH 值对补体替代途径的调节。
DOI：
--
发表时间：
1987
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Fishelson,Z;Horstmann,RD;Müller-Eberhard,HJ
通讯作者：
Müller-Eberhard,HJ
人备解素的分子结构，补体替代途径的正调节剂。
DOI：
--
发表时间：
1984
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Smith,CA;Pangburn,MK;Vogel,CW;Müller-Eberhard,HJ
通讯作者：
Müller-Eberhard,HJ
影响因子：
3.6
作者：
Chen JY;Cortes C;Ferreira VP
通讯作者：
Ferreira VP
人备解素天然聚合形式及其在补体激活中的功能分析。
DOI：
--
发表时间：
1989
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Pangburn,MK
通讯作者：
Pangburn,MK