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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.<\/jats:p>","DOI":"10.1083\/jcb.202411175","type":"journal-article","created":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T02:21:06Z","timestamp":1749867666000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["Evolutionarily diverse caveolins share a common structural framework built around amphipathic disks"],"prefix":"10.1083","volume":"224","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6952-7482","authenticated-orcid":true,"given":"Bing","family":"Han","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0153tk833","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Membrane and Cell Physiology, University of Virginia 1 , Charlottesville, 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