Abstract
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.