Complement system

The complement activation takes place through one or more of the well-established (alternative, classical or lectin) pathways consisting of plasma and membrane-bound proteins. All three pathways converge at the level of complement C3 [https://doi.org/10.6072/H0.MP.A004235.01] and are controlled by regulators [https://doi.org/10.1038/ni.1923]. Complement C3 belongs to the alpha-2-macroglobulin family of proteins, and consists of a alpha-chain and an beta-chain. Cleavage of C3 which can be initiated by one or more of the above three distinct pathways, into C3b[Proteolysis@23-667,749-1663] and C3a [Proteolysis@672-748] is an important step in the complement activation cascade. Classical and lectin pathways, when activated with recognition of pathogens (or immune complexes) use C3-convertase [C4b2a] to cleave complement C3 into C3a and C3b [https://doi.org/10.1084/jem.125.2.359]. However, in alternative pathway a small fraction of the C3 molecules are hydrolyzed to C3(H20) exposing new binding sites. This hydrated C3 [C3(H20)] recruits complement factor B [fB], which is then cleaved by complement factor D [fD] to result in formation of the minor form of C3-convertase [C3(H20)Bb] that cleaves C3 into C3a and C3b [https://doi.org/10.1084/jem.154.3.856]. Further, addition of C3b to C3 convertase [C3bBb or C4b2a] results in C5 convertase [C3bBb3b or C4b2a3b], that cleaves complement C5 to C5a and C5b, is the last enzymatic step of the complement activation cascade [https://doi.org/10.1074/jbc.273.27.16828][https://www.ncbi.nlm.nih.gov/pubmed/?term=2387864]. During complement activation C5b interacts with complement C6, C7, C8 and C9 in a sequential and non-catalyzed manner to result in the formation of Terminal Complement Complex (TCC) [https://doi.org/10.1074/jbc.M111.219766]. The entire network is considered as a simple recognition and elimination system of host-immune complexes and apoptotic and/or pathogens, and therefore promotes host immune homeostasis. The complement system is also involved in cross-talk with other processes related to coagulation, lipid metabolism and cancer. However, many pathogens counteract complement attack through a range of different mechanisms, such acquisition of host complement regulators to the surface of pathogen, or secretion of complement inactivation factors. In order to have a holistic view of the entire complement network, Dr. John D.Lambris group (University of Pennsylvania) developed the Complement Map Database (CMAP) which is a unique repository focused on documented molecular interactions described within the complement cascade and between complement and other biological systems. Information contained in CMAP (http://www.complement.us/cmap/index.php)[https://doi.org/10.1093/bioinformatics/btt269] is entirely based on published experimental data and is fully revised by experts in the field. Further, the Signaling Gateway Molecule Pages -SGMP-( https://escholarship.org/uc/molecule_pages)[https://doi.org/10.1093/bioinformatics/btr190] has published a curated data on each protein involved in human complement activation pathways (refs. [https://doi.org/10.6072/H0.MP.A004235.01] [https://doi.org/10.6072/H0.MP.A004228.01] [https://doi.org/10.6072/H0.MP.A004276.01] [https://doi.org/10.6072/H0.MP.A004256.01] [https://doi.org/10.6072/H0.MP.A004240.01] [https://doi.org/10.6072/H0.MP.A008392.01] [https://doi.org/10.6072/H0.MP.A008391.01] [https://doi.org/10.6072/H0.MP.A004274.01] [https://doi.org/10.6072/H0.MP.A004275.01] [https://doi.org/10.6072/H0.MP.A004266.01] [https://doi.org/10.6072/H0.MP.A004267.01] [https://doi.org/10.6072/H0.MP.A004263.01] [https://doi.org/10.6072/H0.MP.A004234.01] [https://doi.org/10.6072/H0.MP.A004258.01] ).

补体激活过程通过一组已确立的途径（包括替代性、经典性或凝集素途径）进行，这些途径由血浆和膜结合蛋白组成。三者均在补体C3水平上汇聚[https://doi.org/10.6072/H0.MP.A004235.01]，并受调节因子[https://doi.org/10.1038/ni.1923]的调控。补体C3隶属于α2-巨球蛋白家族，由α链和β链构成。C3的裂解，可由上述三种途径之一或多个触发，形成C3b[蛋白酶解@23-667,749-1663]和C3a[蛋白酶解@672-748]，是补体激活级联反应中的关键步骤。在经典性和凝集素途径被激活，并识别病原体（或免疫复合物）时，利用C3转化酶[C4b2a]将补体C3裂解为C3a和C3b[https://doi.org/10.1084/jem.125.2.359]。然而，在替代途径中，一小部分C3分子被水解为C3(H2O)，暴露出新的结合位点。这种水合C3[C3(H2O)]招募补体因子B[fB]，随后被补体因子D[fD]裂解，形成C3-转化酶的亚型——C3(H2O)Bb，该亚型将C3裂解为C3a和C3b[https://doi.org/10.1084/jem.154.3.856]。此外，将C3b添加至C3转化酶[C3bBb或C4b2a]上，可形成C5转化酶[C3bBb3b或C4b2a3b]，该酶将补体C5裂解为C5a和C5b，这是补体激活级联反应中的最后一步酶促过程[https://doi.org/10.1074/jbc.273.27.16828][https://www.ncbi.nlm.nih.gov/pubmed/?term=2387864]。在补体激活过程中，C5b依次与非催化性地与补体C6、C7、C8和C9相互作用，最终形成终末补体复合物（TCC）[https://doi.org/10.1074/jbc.M111.219766]。整个网络被视为宿主-免疫复合物、凋亡和/或病原体的简单识别与清除系统，从而促进宿主免疫稳态。补体系统还涉及与其他过程的相关性，如凝血、脂质代谢和癌症。然而，许多病原体通过多种机制对抗补体攻击，例如将宿主补体调节因子获取至病原体表面，或分泌补体失活因子。为了全面审视整个补体网络，约翰·D·拉姆布里斯博士（宾夕法尼亚大学）的研究团队开发了补体图谱数据库（CMAP），这是一个独特的存储库，专注于记录补体级联反应内及其与其他生物系统之间的分子相互作用。CMAP（http://www.complement.us/cmap/index.php)[https://doi.org/10.1093/bioinformatics/btt269]中的信息完全基于已发表的实验数据，并由该领域的专家进行全面修订。此外，信号通路门控分子页面——SGMP-(https://escholarship.org/uc/molecule_pages)[https://doi.org/10.1093/bioinformatics/btr190]已发布有关参与人类补体激活途径的每种蛋白质的精选数据（参考文献[https://doi.org/10.6072/H0.MP.A004235.01] [https://doi.org/10.6072/H0.MP.A004228.01] [https://doi.org/10.6072/H0.MP.A004276.01] [https://doi.org/10.6072/H0.MP.A004256.01] [https://doi.org/10.6072/H0.MP.A004240.01] [https://doi.org/10.6072/H0.MP.A008392.01] [https://doi.org/10.6072/H0.MP.A008391.01] [https://doi.org/10.6072/H0.MP.A004274.01] [https://doi.org/10.6072/H0.MP.A004275.01] [https://doi.org/10.6072/H0.MP.A004266.01] [https://doi.org/10.6072/H0.MP.A004267.01] [https://doi.org/10.6072/H0.MP.A004263.01] [https://doi.org/10.6072/H0.MP.A004234.01] [https://doi.org/10.6072/H0.MP.A004258.01])。