Fungal plasma membrane proteins represent key therapeutic targets for antifungal agents, yet their structure and spatial distribution in the native context remain poorly characterized. Herein, we employ an integrative multimodal approach to elucidate the structural and functional organization of plasma membrane protein complexes in Candida glabrata, focusing on prominent and essential membrane proteins, the polysaccharide synthase beta-(1,3)-glucan synthase (GS), and the proton pump Pma1. Cryo-electron tomography (cryo-ET) and live cell imaging reveal that treatment with caspofungin, an echinocandin antifungal that targets GS, disrupts the native distribution of fungal membrane complexes and alters the biophysical properties of the plasma membrane. Perturbation of the sphingolipid biosynthesis pathway further modulates susceptibility to the drug. Based on these findings, we propose a model of how the plasma membrane context plays an integral role in the higher-order organization of membrane proteins and echinocandin inhibition of GS. Our work underscores the importance of interrogating the structural and dynamic characteristics of fungal plasma membrane proteins in their native membrane environment to understand their function and facilitate the development of novel antifungal therapies that precisely target GS.
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: integrative structural biology ; cryo-electron tomography (cryo-ET) ; fungal plasma membrane proteins ; echinocandins ; DatasetType:Proteomics
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Wei Dai, Rutgers University, United States |
| Submitting User: | haiyanzheng |
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