An unfolded CH1 domain controls the assembly and secretion of IgG antibodies.
An unfolded CH1 domain controls the assembly and secretion of IgG antibodies.
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DOI：
10.1016/j.molcel.2009.04.028
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发表时间：
2009-06-12
期刊：
影响因子：
16
通讯作者：
Buchner, Johannes
中科院分区：
文献类型：
--
作者：
Feige, Matthias J.;Groscurth, Sandra;Marcinowski, Moritz;Shimizu, Yuichiro;Kessler, Horst;Hendershot, Linda M.;Buchner, Johannes
抗体分泌和功能的先决条件是组装成一个确定的四级结构，由IgG的两条重链和两条轻链组成。未组装的重链主动保留在内质网（ER）中，直到它们与轻链结合。我们对这一关键质量控制步骤的机制分析表明，与所研究的所有其他抗体结构域不同，小鼠IgG1重链的CH1结构域是一种内在无序的分离蛋白。它仅在与其同源伙伴CL结构域相互作用时才采用典型的免疫球蛋白折叠。结构形成通过一个被捕获的中间体进行，可以被er特异性肽基脯氨酸异构酶亲环蛋白B加速，并由分子伴侣BiP调节。BiP识别CH1结构域的不完全折叠状态，并竞争与CL结构域的结合。体内实验表明，体外折叠CH1结构域的要求，包括与折叠的CL结构域的结合和保守脯氨酸残基的异构化，是细胞内抗体组装和分泌所必需的。
A prerequisite for antibody secretion and function is the assembly into a defined quaternary structure, composed of two heavy and two light chains for IgG. Unassembled heavy chains are actively retained in the endoplasmic reticulum (ER) until they associate with light chains. Our mechanistic analysis of this critical quality control step revealed that, unlike all other antibody domains studied, the CH1 domain of the murine IgG1 heavy chain is an intrinsically disordered protein in isolation. It adopts the typical immunoglobulin fold only upon interaction with its cognate partner, the CL domain. Structure formation proceeds via a trapped intermediate, can be accelerated by the ER-specific peptidyl-prolyl isomerase cyclophilin B, and is modulated by the molecular chaperone BiP. BiP recognizes incompletely folded states of the CH1 domain and competes for binding to the CL domain. In vivo experiments demonstrate that requirements identified for folding the CH1 domain in vitro, including association with a folded CL domain and isomerization of a conserved proline residue, are essential for antibody assembly and secretion in the cell.
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