Structural basis for CD97 recognition of the decay-accelerating factor CD55 suggests mechanosensitive activation of adhesion GPCRs.
Structural basis for CD97 recognition of the decay-accelerating factor CD55 suggests mechanosensitive activation of adhesion GPCRs.
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CD97 识别衰变加速因子 CD55 的结构基础表明粘附 GPCR 的机械敏感激活
DOI：
10.1016/j.jbc.2021.100776
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Song G
中科院分区：
文献类型：
--
作者：
Niu M;Xu S;Yang J;Yao D;Li N;Yan J;Zhong G;Song G
粘附G蛋白偶联受体CD 97及其配体补体衰变加速因子CD 55是人类免疫系统中重要的结合伴侣。这种结合的功能障碍与免疫疾病有关，如多发性硬化症和类风湿性关节炎，以及各种癌症。已有文献表明，CD 97在其N端包含3 - 5个表皮生长因子（EGF）结构域，这些EGF结构域可与CD 55的N端短共有重复序列（SCR）结构域结合。然而，这种相互作用的细节仍然难以捉摸，特别是为什么CD 55以最高的亲和力与CD 97的最短同种型（EGF 1，2，5）结合。在此，我们设计了一种嵌合表达构建体，其中CD 97的EGF 1、2、5结构域和CD 55的SCR 1 -4结构域通过柔性接头连接，并通过晶体学确定了复合物结构。我们的数据显示，这两种蛋白质采用整体反平行结合模式，涉及CD 55的SCR 1 -3结构域和CD 97的所有三个EGF结构域。突变数据证实了EGF 5在相互作用中的重要性，并解释了CD 55和CD 97之间的结合特异性。CD 55-CD 97结合模式的结构以及动力学表明，在循环环境中，当力施加到两种蛋白质的C末端时，力抵抗剪切拉伸几何形状。CD 55-CD 97复合物承受张力的潜力可能为粘附G蛋白偶联受体激活的机械传感机制提供基础。
The adhesion G protein–coupled receptor CD97 and its ligand complement decay-accelerating factor CD55 are important binding partners in the human immune system. Dysfunction in this binding has been linked to immune disorders such as multiple sclerosis and rheumatoid arthritis, as well as various cancers. Previous literatures have indicated that the CD97 includes 3 to 5 epidermal growth factor (EGF) domains at its N terminus and these EGF domains can bind to the N-terminal short consensus repeat (SCR) domains of CD55. However, the details of this interaction remain elusive, especially why the CD55 binds with the highest affinity to the shortest isoform of CD97 (EGF1,2,5). Herein, we designed a chimeric expression construct with the EGF1,2,5 domains of CD97 and the SCR1–4 domains of CD55 connected by a flexible linker and determined the complex structure by crystallography. Our data reveal that the two proteins adopt an overall antiparallel binding mode involving the SCR1–3 domains of CD55 and all three EGF domains of CD97. Mutagenesis data confirmed the importance of EGF5 in the interaction and explained the binding specificity between CD55 and CD97. The architecture of CD55–CD97 binding mode together with kinetics suggests a force-resisting shearing stretch geometry when forces applied to the C termini of both proteins in the circulating environment. The potential of the CD55–CD97 complex to withstand tensile force may provide a basis for the mechanosensing mechanism for activation of adhesion G protein–coupled receptors.
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影响因子：
--
作者：
Jaspars, LH;Vos, W;Hamann, J
通讯作者：
Hamann, J
影响因子：
--
作者：
Hoek, Robert M.;de launay, Daphne;Hamann, Jorg
通讯作者：
Hamann, Jorg
影响因子：
11.4
作者：
Arac, Demet;Boucard, Antony A.;Bolliger, Marc F.;Nguyen, Jenna;Soltis, S. Michael;Suedhof, Thomas C.;Brunger, Axel T.
通讯作者：
Brunger, Axel T.
影响因子：
4.4
作者：
Karpus, Olga N.;Veninga, Henrike;Hamann, Jorg
通讯作者：
Hamann, Jorg
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH