Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12839-44. doi: 10.1073/pnas.1102167108. Epub 2011 Jul 18.
The complement system is a key component of innate and adaptive immune responses. Complement regulation is critical for prevention and control of disease. We have determined the crystal structure of the complement regulatory enzyme human factor I (fI). FI is in a proteolytically inactive form, demonstrating that it circulates in a zymogen-like state despite being fully processed to the mature sequence. Mapping of functional data from mutants of fI onto the structure suggests that this inactive form is maintained by the noncatalytic heavy-chain allosterically modulating activity of the light chain. Once the ternary complex of fI, a cofactor and a substrate is formed, the allosteric inhibition is released, and fI is oriented for cleavage. In addition to explaining how circulating fI is limited to cleaving only C3b/C4b, our model explains the molecular basis of disease-associated polymorphisms in fI and its cofactors.
补体系统是先天和适应性免疫反应的关键组成部分。补体调节对于疾病的预防和控制至关重要。我们已经确定了补体调节酶人因子 I（fI）的晶体结构。FI 处于无蛋白水解活性形式，表明尽管已完全加工成熟序列，但它仍以酶原样状态循环。将 fI 突变体的功能数据映射到结构上表明，这种无活性形式是通过非催化重链变构调节轻链活性来维持的。一旦形成 fI、辅助因子和底物的三元复合物，变构抑制就会释放，fI 就会被定向切割。除了解释循环中的 fI 如何仅限于切割 C3b/C4b 之外，我们的模型还解释了 fI 及其辅助因子中与疾病相关的多态性的分子基础。
