Cryo-EM architecture of a near-native stretch-sensitive membrane microdomain

Jennifer M. Kefauver, Markku Hakala, Luoming Zou, Josephine Alba, Javier Espadas, Maria G. Tettamanti, Jelena Gajić, Caroline Gabus, Pablo Campomanes, Leandro F. Estrozi, Nesli E. Sen, Stefano Vanni, Aurélien Roux, Ambroise Desfosses and Robbie Loewith ()
Additional contact information
Jennifer M. Kefauver: University of Geneva
Markku Hakala: University of Geneva
Luoming Zou: University of Geneva
Josephine Alba: University of Fribourg
Javier Espadas: University of Geneva
Maria G. Tettamanti: University of Geneva
Jelena Gajić: University of Geneva
Caroline Gabus: University of Geneva
Pablo Campomanes: University of Fribourg
Leandro F. Estrozi: Université Grenoble Alpes, CEA, CNRS, IBS
Nesli E. Sen: University of Geneva
Stefano Vanni: University of Fribourg
Aurélien Roux: University of Geneva
Ambroise Desfosses: Université Grenoble Alpes, CEA, CNRS, IBS
Robbie Loewith: University of Geneva

Nature, 2024, vol. 632, issue 8025, 664-671

Abstract: Abstract Biological membranes are partitioned into functional zones termed membrane microdomains, which contain specific lipids and proteins1–3. The composition and organization of membrane microdomains remain controversial because few techniques are available that allow the visualization of lipids in situ without disrupting their native behaviour3,4. The yeast eisosome, composed of the BAR-domain proteins Pil1 and Lsp1 (hereafter, Pil1/Lsp1), scaffolds a membrane compartment that senses and responds to mechanical stress by flattening and releasing sequestered factors5–9. Here we isolated near-native eisosomes as helical tubules made up of a lattice of Pil1/Lsp1 bound to plasma membrane lipids, and solved their structures by helical reconstruction. Our structures reveal a striking organization of membrane lipids, and, using in vitro reconstitutions and molecular dynamics simulations, we confirmed the positioning of individual PI(4,5)P2, phosphatidylserine and sterol molecules sequestered beneath the Pil1/Lsp1 coat. Three-dimensional variability analysis of the native-source eisosomes revealed a dynamic stretching of the Pil1/Lsp1 lattice that affects the sequestration of these lipids. Collectively, our results support a mechanism in which stretching of the Pil1/Lsp1 lattice liberates lipids that would otherwise be anchored by the Pil1/Lsp1 coat, and thus provide mechanistic insight into how eisosome BAR-domain proteins create a mechanosensitive membrane microdomain.

Date: 2024
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DOI: 10.1038/s41586-024-07720-6

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