Structure of the C1r-C1s interaction of the C1 complex of complement activation.
Structure of the C1r-C1s interaction of the C1 complex of complement activation.
复制标题
DOI：
10.1073/pnas.1718709115
复制
发表时间：
2018-01-23
影响因子：
11.1
通讯作者：
Wallis R
中科院分区：
文献类型：
--
作者：
Almitairi JOM;Venkatraman Girija U;Furze CM;Simpson-Gray X;Badakshi F;Marshall JE;Schwaeble WJ;Mitchell DA;Moody PCE;Wallis R
C1是一个大的复合物，通过裂解或刺激先天性和适应性免疫过程来触发入侵病原体的破坏。它由C1 q（一种具有花束状结构的蛋白质）以及由丝氨酸蛋白酶C1 r和C1 s的两个拷贝组装而成的四聚体组成，当C1 q与病原体表面结合时，丝氨酸蛋白酶C1 r和C1 s激活。在这里，我们描述了详细的结构，显示C1 r和C1 s如何通过一个广泛的界面，包括两种蛋白酶的N-末端区域的相互作用。我们的研究结果揭示了蛋白酶四聚体是如何组织的，并提出了C1的组装和激活机制。多蛋白复合物C1在与抗体-抗原复合物、病原体表面、凋亡细胞和聚阴离子结构结合时启动补体活化的经典途径。它是由识别子组分C1 q和蛋白酶C1 r2 C1 s2的四聚体作为Ca 2+依赖性复合物形成的。在这里，我们已经确定了C1 r和C1 s的CUB 1-EGF-CUB 2片段之间的复合物的结构，以揭示形成C1核心的C1 r-C1 s相互作用。这两个片段是L形的和联锁，形成一个紧凑的反平行的异源二聚体与Ca 2+从每个子组件在界面处。接触，涉及所有三个领域的每种蛋白酶，是更广泛的比C1 R或C1 S同源二聚体，解释为什么杂合物的形式优先。现有的结构和生物物理数据支持C1 r2 C1 s2模型，其中两个C1 r-C1 s二聚体通过C1 r的催化结构域连接。他们是不兼容的最近的模型，其中的N-末端结构域的C1 r和C1 s形成一个固定的四聚体。在与C1 q结合时，蛋白酶变得更加紧凑，C1 r-C1 s二聚体位于中心，C1 q的六个胶原茎围绕周边排列。当C1 q与表面结合时，激活可能由C1 r-C1 s二聚体对的分离驱动。C1 s的相当大的灵活性可能有助于C1复合物的形成，C1 r对C1 s的激活，以及下游底物C4和C4 b结合的C2的结合和激活，以启动反应级联。
C1 is a large complex that triggers the destruction of invading pathogens via lysis or by stimulation of innate and adaptive immune processes. It is composed of C1q, a protein with a bouquet-like architecture, together with a tetramer assembled from two copies each of the serine proteases C1r and C1s, which activate when C1q binds to a pathogen surface. Here we describe detailed structures that show how C1r and C1s interact via an extensive interface encompassing the N-terminal regions of both proteases. Our findings reveal how the protease tetramer is organized and suggest a mechanism for the assembly and activation of C1. The multiprotein complex C1 initiates the classical pathway of complement activation on binding to antibody–antigen complexes, pathogen surfaces, apoptotic cells, and polyanionic structures. It is formed from the recognition subcomponent C1q and a tetramer of proteases C1r2C1s2 as a Ca2+-dependent complex. Here we have determined the structure of a complex between the CUB1-EGF-CUB2 fragments of C1r and C1s to reveal the C1r–C1s interaction that forms the core of C1. Both fragments are L-shaped and interlock to form a compact antiparallel heterodimer with a Ca2+ from each subcomponent at the interface. Contacts, involving all three domains of each protease, are more extensive than those of C1r or C1s homodimers, explaining why heterocomplexes form preferentially. The available structural and biophysical data support a model of C1r2C1s2 in which two C1r-C1s dimers are linked via the catalytic domains of C1r. They are incompatible with a recent model in which the N-terminal domains of C1r and C1s form a fixed tetramer. On binding to C1q, the proteases become more compact, with the C1r-C1s dimers at the center and the six collagenous stems of C1q arranged around the perimeter. Activation is likely driven by separation of the C1r-C1s dimer pairs when C1q binds to a surface. Considerable flexibility in C1s likely facilitates C1 complex formation, activation of C1s by C1r, and binding and activation of downstream substrates C4 and C4b-bound C2 to initiate the reaction cascade.
登录
查看更多内容
DOI：
10.1016/j.str.2016.12.014
发表时间：
2017-02-07
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Nan R;Furze CM;Wright DW;Gor J;Wallis R;Perkins SJ
通讯作者：
Perkins SJ
DOI：
10.4049/jimmunol.0900666
发表时间：
2009-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Phillips AE;Toth J;Dodds AW;Girija UV;Furze CM;Pala E;Sim RB;Reid KB;Schwaeble WJ;Schmid R;Keeble AH;Wallis R
通讯作者：
Wallis R
影响因子：
7.3
作者：
Gaboriaud C;Ling WL;Thielens NM;Bally I;Rossi V
通讯作者：
Rossi V
DOI：
10.1073/pnas.79.2.586
发表时间：
1982-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
STRANG, CJ;SIEGEL, RC;SCHUMAKER, VN
通讯作者：
SCHUMAKER, VN
影响因子：
56.9
作者：
BELLA, J;EATON, M;BERMAN, HM
通讯作者：
BERMAN, HM