小柯机器人

Wnt生物发生、分泌和Wnt7特异信号的分子基础，这一成果由美国德克萨斯大学西南医学中心Xiaochun Li 、Xiaofeng Qi团队经过不懈努力而取得。相关论文于2023年10月17日发表在国际学术期刊《细胞》上。

Wnt7a是一种参与中枢神经系统血管生成和血脑屏障维持的重要Wnt蛋白，通过对Wnt7a结构和功能的分析，研究人员阐明了Wnt生成和Wnt7特异性信号转导的原理。Wnt7a- Wntless（WLS）复合物与calreticulin（CALR）结合，表明CALR在Wnt生物发生过程中作为伴侣蛋白促进Wnt从Porcupine（PORCN）转移到WLS。

结构、功能分析和分子动力学模拟证明，Wnt与WLS核心中的磷脂结合调节Wnt和WLS之间的结合和解离，揭示了一种脂质介导Wnt分泌的机制。最后，Wnt7a与细胞表面Wnt7共受体RECK结合的结构，揭示了RECKCC4与Wnt7a的N端结构域结合以激活Wnt7特异性信号传导的机制。

据悉，Wnt蛋白在ER中被PORCN酶脂化，并与WLS结合进行细胞内运输和分泌。这些低溶解度Wnts从ER转移到细胞外基质的机制仍不清楚。

附：英文原文

Title: Molecular basis of Wnt biogenesis, secretion, and Wnt7-specific signaling

Author: Xiaofeng Qi, Qinli Hu, Nadia Elghobashi-Meinhardt, Tao Long, Hongwen Chen, Xiaochun Li

Issue&Volume: 2023-10-17

Abstract: Wnt proteins are enzymatically lipidated by Porcupine (PORCN) in the ER and bind toWntless (WLS) for intracellular transport and secretion. Mechanisms governing thetransfer of these low-solubility Wnts from the ER to the extracellular space remainunclear. Through structural and functional analyses of Wnt7a, a crucial Wnt involvedin central nervous system angiogenesis and blood-brain barrier maintenance, we haveelucidated the principles of Wnt biogenesis and Wnt7-specific signaling. The Wnt7a-WLScomplex binds to calreticulin (CALR), revealing that CALR functions as a chaperoneto facilitate Wnt transfer from PORCN to WLS during Wnt biogenesis. Our structures,functional analyses, and molecular dynamics simulations demonstrate that a phospholipidin the core of Wnt-bound WLS regulates the association and dissociation between Wntand WLS, suggesting a lipid-mediated Wnt secretion mechanism. Finally, the structureof 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.

DOI: 10.1016/j.cell.2023.09.021

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01075-9