TY - JOUR
T1 - Two structural and functional domains of MESD required for proper folding and trafficking of LRP5/6
AU - Chen, Jianglei
AU - Liu, Chia Chen
AU - Li, Qianqian
AU - Nowak, Christian
AU - Bu, Guojun
AU - Wang, Jianjun
N1 - Funding Information:
This work is supported by NIH RO1 grants (HL 074365 and HL 076620 to J.W., and AG027924 to G.B.). The authors also thank Ms Victoria Murray for critical reading of the manuscript.
PY - 2011/3/9
Y1 - 2011/3/9
N2 - 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.
AB - 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.
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U2 - 10.1016/j.str.2011.01.010
DO - 10.1016/j.str.2011.01.010
M3 - Article
C2 - 21397183
AN - SCOPUS:79952470911
SN - 0969-2126
VL - 19
SP - 313
EP - 323
JO - Structure with Folding & design
JF - Structure with Folding & design
IS - 3
ER -