Design principles of caveolins across metazoa and beyond

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 disc 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, a unicellular relative to animals. This analysis revealed seven conserved structural elements and a propensity to assemble into amphipathic discs. Despite extreme sequence variability, new cryo-EM structures of caveolins from the 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 evolutionary branches where caveolins translocated and expanded, including a parahoxozoan ancestral chromosome as the origin of most caveolin diversity. 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.