Understanding Periperal Membrane Protein Interactions | BPS Thematic Meeting

Understanding Peripheral Membrane Protein Interactions: Structure, Dynamics, Function and Therapy

Poster Abstracts

15-POS Board 15 CAVEOLINS: HIDING IN MEMBRANES AND GENOMES Randall Schirra ; Anne Kenworthy 1 ; Yelena T Peskova 1 ; Ajit Tiwari 1 ; Bing Han 1 ; 1 University of Virginia, Molecular Physiology and Biological Physics, Charlottesville, VA, USA Caveolae are flask-shaped membrane invaginations defined by caveolin proteins, a structurally unique and, until recently, thought to be animal-restricted protein family. Caveolin-1 plays critical roles in lipid trafficking, mechanotransduction, and nitric oxide signaling, yet its molecular mechanisms remain poorly understood. Any insight into its structure-function relationship could illuminate details underlying human disease. Recent structural breakthroughs by our group, in collaboration with the Ohi and Karakas Labs, revealed the first complete structure of human Cav-1 and a newly discovered homolog from the choanoflagellate Salpingoeca rosetta. Both adopt a unique undecameric amphipathic disc architecture that displaces ~45 nm² of the plasma membrane’s inner leaflet. Inspired by the discovery of S. rosetta Cav, we began a broad search for caveolin ancestors that can help illuminate the mechanisms of caveolins. New and powerful tools such as FoldSeek and AlphaFind promise to uncover structurally homologous proteins using sequence-free methods. However, for caveolin, which has a simple tertiary structure but a unique quaternary structure, these tools are not yet optimized for such a task. Here, we have developed a pipeline combining large-scale BLAST searches with AlphaFold-based quaternary structure prediction to identify caveolin-like sequences in public databases such as the National Center for Biotechnology Information (NCBI). This integrated pipeline enables the identification of caveolin-like proteins that may have been overlooked by traditional sequence-based searches, potentially expanding our understanding of membrane protein evolution. Thus far, we have uncovered over twenty caveolin-like proteins from diverse species that have yet to be annotated as Caveolin. Despite moderate sequence identity, these proteins are predicted to exhibit striking structural conservation, forming the same undecameric amphipathic disc architecture. Our data suggests that caveolins are far older and more ubiquitous than previously believed. These homologs could help us gain key insights into the fundamental biology of the caveolin protein family.

60