Han Bing, Connolly Sarah M, Schultz Darrin T, Wilson Louis F L, Gulsevin Alican, Meiler Jens, Karakas Erkan, Ohi Melanie D, Kenworthy Anne K
Center for Membrane and Cell Physiology, University of Virginia , Charlottesville, VA, USA.
Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA.
J Cell Biol. 2025 Sep 1;224(9). doi: 10.1083/jcb.202411175. Epub 2025 Aug 7.
Caveolins are a unique family of membrane remodeling proteins present broadly across animals (Metazoa), and in vertebrates form flask-shaped invaginations known as caveolae. While human caveolin-1 assembles into an amphipathic disk composed of 11 spirally packed protomers, the structural basis underlying caveolin function across animals remains elusive. Here, we predicted structures for 73 caveolins spanning animal diversity, as well as a newly identified choanoflagellate caveolin from Salpingoeca rosetta. This analysis revealed seven conserved structural elements and a propensity to assemble into amphipathic disks. Cryo-EM structures of caveolins from S. rosetta choanoflagellate and the purple sea urchin Strongylocentrotus purpuratus exhibit striking structural similarities to human caveolin-1, validating the structural predictions. Lastly, tracing the chromosomal evolutionary history of caveolins revealed its parahoxozoan ancestral chromosome and evolutionary branches on which caveolins translocated and expanded. These results show that caveolins possess an ancient structural framework predating Metazoa and provide a new structural paradigm to explore the molecular basis of caveolin function across diverse evolutionary lineages.
小窝蛋白是一类独特的膜重塑蛋白家族，广泛存在于动物界（后生动物），在脊椎动物中形成称为小窝的烧瓶状内陷结构。虽然人类小窝蛋白-1组装成由11个螺旋排列的原聚体组成的两亲性盘状物，但动物界中小窝蛋白功能的结构基础仍然难以捉摸。在这里，我们预测了跨越动物多样性的73种小窝蛋白的结构，以及从玫瑰旋轮虫新鉴定出的领鞭毛虫小窝蛋白。该分析揭示了七个保守的结构元件以及组装成两亲性盘状物的倾向。来自玫瑰旋轮虫领鞭毛虫和紫海胆的小窝蛋白的冷冻电镜结构与人类小窝蛋白-1表现出惊人的结构相似性，验证了结构预测。最后，追溯小窝蛋白的染色体进化历史揭示了其副同源动物祖先染色体以及小窝蛋白易位和扩展的进化分支。这些结果表明，小窝蛋白拥有一个早于后生动物的古老结构框架，并为探索不同进化谱系中小窝蛋白功能的分子基础提供了一个新的结构范式。
