Wnt信号通路
生物
生物发生
细胞生物学
分泌物
细胞外
信号转导
生物化学
基因
作者
Xiaofeng Qi,Qinli Hu,Nadia Elghobashi-Meinhardt,Tao Long,Hongwen Chen,Xiaochun Li
出处
期刊:Cell
[Elsevier]
日期:2023-10-17
卷期号:186 (23): 5028-5040.e14
被引量:11
标识
DOI:10.1016/j.cell.2023.09.021
摘要
Wnt proteins are enzymatically lipidated by Porcupine (PORCN) in the ER and bind to Wntless (WLS) for intracellular transport and secretion. Mechanisms governing the transfer of these low-solubility Wnts from the ER to the extracellular space remain unclear. Through structural and functional analyses of Wnt7a, a crucial Wnt involved in central nervous system angiogenesis and blood-brain barrier maintenance, we have elucidated the principles of Wnt biogenesis and Wnt7-specific signaling. The Wnt7a-WLS complex binds to calreticulin (CALR), revealing that CALR functions as a chaperone to facilitate Wnt transfer from PORCN to WLS during Wnt biogenesis. Our structures, functional analyses, and molecular dynamics simulations demonstrate that a phospholipid in the core of Wnt-bound WLS regulates the association and dissociation between Wnt and WLS, suggesting a lipid-mediated Wnt secretion mechanism. Finally, the structure of Wnt7a bound to RECK, a cell-surface Wnt7 co-receptor, reveals how RECKCC4 engages the N-terminal domain of Wnt7a to activate Wnt7-specific signaling.
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