Cryo-EM structure and oligomerization of the human planar cell polarity core protein Vangl1

作者：Fan Zhang, Shaobai Li, Hao Wu, Shanshuang Chen · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-024-55397-2 · 被引用次数：11 · 研究领域：Wnt/β-catenin signaling in development and cancer、RNA Research and Splicing、Heat shock proteins research

Vangl is a planar cell polarity (PCP) core protein essential for aligned cell orientation along the epithelial plane perpendicular to the apical-basal direction, which is important for tissue morphogenesis, development and collective cell behavior. Mutations in Vangl are associated with developmental defects, including neural tube defects (NTDs), according to human cohort studies of sporadic and familial cases. The complex mechanisms underlying Vangl-mediated PCP signaling or Vangl-associated human congenital diseases have been hampered by the lack of molecular characterizations of Vangl. Here, we show biochemical and structural evidence that human Vangl1 oligomerizes as dimers of trimers, and that the dimerization of trimers promotes binding to the PCP effector Prickle1 (Pk1) in vitro. Mapping of human disease-associated point mutations suggests potential pathological mechanisms and paves the way for future studies on the importance of lipid binding, central vestibule and oligomerization of Vangl, thereby providing insights into the molecular mechanisms of the PCP signaling pathway. The authors present a cryo-EM structure of human planar cell polarity core protein Vangl1, revealing a dimer-of-trimers architecture, clarifying how Vangl1 may interact with effector proteins to mediate PCP signaling and potential pathological mechanisms for human disease-related mutations.