Department of Biochemistry and Molecular Biology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Structure. 2011 Mar 9;19(3):313-23. doi: 10.1016/j.str.2011.01.010.
How the endoplasmic reticulum (ER) folding machinery coordinates general and specialized chaperones during protein translation and folding remains an important unanswered question. Here, we show two structural domains in MESD, a specialized chaperone for LRP5/6, carry out dual functions. The chaperone domain forms a complex with the immature receptor, maintaining the β-propeller (BP) domain in an interaction competent state for epidermal growth factor-repeat binding. This promotes proper folding of the BP domain, causing a binding switch from the chaperone domain to the escort domain. The escort complex ensures LRP5/6 safe-trafficking from the ER to the Golgi by preventing premature ligand-binding. Inside the Golgi, the BP domain may contain a histidine switch, regulating MESD dissociation and retrieval. Together, we generate a plausible cell biology picture of the MESD/LRP5/6 pathway, suggesting that it is the specialized chaperones, MESD, that serves as the folding template to drive proper folding and safe trafficking of large multidomain proteins LRP5/6.
内质网（ER）折叠机制如何在蛋白质翻译和折叠过程中协调通用和专用伴侣蛋白，这仍然是一个重要的未解决的问题。在这里，我们展示了 LRP5/6 的专用伴侣蛋白 MESD 中的两个结构域具有双重功能。伴侣结构域与未成熟的受体形成复合物，使β-螺旋桨（BP）结构域保持与表皮生长因子重复结合的相互作用状态。这促进了 BP 结构域的正确折叠，导致从伴侣结构域到护送结构域的结合转换。护送复合物通过防止配体的过早结合来确保 LRP5/6 从 ER 安全运输到高尔基体。在高尔基体内部，BP 结构域可能含有组氨酸开关，调节 MESD 的解离和回收。综上所述，我们提出了 MESD/LRP5/6 途径的一个合理的细胞生物学图景，表明正是专用伴侣蛋白 MESD 充当折叠模板，驱动大型多结构域蛋白 LRP5/6 的正确折叠和安全运输。
