PT - JOURNAL ARTICLE AU - Bing Han AU - Alican Gulsevin AU - Sarah Connolly AU - Ting Wang AU - Jason Porta AU - Ajit Tiwari AU - Angie Deng AU - Louise Chang AU - Yelena Peskova AU - Hassane S. Mchaoraub AU - Erkan Karakas AU - Melanie D. Ohi AU - Jens Meiler AU - Anne K. Kenworthy TI - Structural characterization of a breast cancer-associated mutation in caveolin-1 AID - 10.1101/2022.05.23.493104 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.05.23.493104 4099 - http://biorxiv.org/content/early/2022/05/23/2022.05.23.493104.short 4100 - http://biorxiv.org/content/early/2022/05/23/2022.05.23.493104.full AB - Caveolin-1 (CAV1) is a membrane sculpting protein that oligomerizes to generate flask-shaped invaginations of the plasma membrane known as caveolae. Mutations in CAV1 have been linked to multiple diseases in humans. Such mutations often interfere with oligomerization and the intracellular trafficking processes required for successful caveolae assembly, but the molecular mechanisms underlying these defects have not been structurally explained. Here, we investigate how a breast cancer-associated mutation in one of the most highly conserved residues in CAV1, P132L, affects CAV1 structure and oligomerization. We show that P132 is positioned at a major site of protomer-protomer interactions within the CAV1 complex, providing a structural explanation for why the mutant protein fails to homo-oligomerize correctly. Using a combination of computational, structural, biochemical, and cell biological approaches, we find that despite its homo-oligomerization defects P132L is capable of forming mixed hetero-oligomeric complexes with wild type CAV1 and that these complexes can be incorporated into caveolae. These findings provide insights into the fundamental mechanisms that control the formation of homo- and hetero-oligomers of caveolins that are essential for caveolae biogenesis, as well as how these processes are disrupted in human disease.Competing Interest StatementThe authors have declared no competing interest.