Design principles of caveolins across metazoa and beyond

Abstract

Caveolins are a unique family of membrane remodeling proteins essential for building flaskshaped nanoscale plasma membrane invaginations that regulate signaling and stress responses in vertebrates known as caveolae. Recent evidence suggests that to generate caveolae, human caveolin-1 assembles into amphipathic disc-shaped complexes consisting of 11 tightly packed, spirally organized protomers. Interestingly, caveolins are expressed broadly throughout Metazoa, including in organisms that lack conventional caveolae. The structural features of caveolins that control their functionality in diverse organisms have yet to be established. To address this fundamental question, we use AlphaFold2 as a predictive tool to investigate the structural properties of 72 representative caveolins across evolution. The results of this analysis reveal caveolins consist of six common structural elements that can be mixed and matched, uncover principles that govern their assembly into oligomeric discs, and provide evidence that the association of caveolins with membranes is one of the most ancient functions of the protein. We also identify homologs of caveolins in choanoflagellates, pointing to a pre-metazoan origin of the protein family. Together, these findings define a new structure-based framework for probing the functional roles of caveolins across evolutionary space.