National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM135343
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
HL160487
米国
Welch Foundation
I-1957
米国
引用
ジャーナル: Cell / 年: 2023 タイトル: Molecular basis of Wnt biogenesis, secretion, and Wnt7-specific signaling. 著者: Xiaofeng Qi / Qinli Hu / Nadia Elghobashi-Meinhardt / Tao Long / Hongwen Chen / Xiaochun Li / 要旨: 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 ...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 RECK engages the N-terminal domain of Wnt7a to activate Wnt7-specific signaling.