Protein-lipid interaction at low pH induces oligomerization of the MakA cytotoxin from Vibrio cholerae.
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Nadeem A, Berg A, Pace H, Alam A, Toh E, Ådén J, Zlatkov N, Myint SL, Persson K, Gröbner G, Sjöstedt A, Bally M, Barandun J, Uhlin BE, Wai SN
Elife 11 (-) - [2022-02-08; online 2022-02-08]
The α-pore-forming toxins (α-PFTs) from pathogenic bacteria damage host cell membranes by pore formation. We demonstrate a remarkable, hitherto unknown mechanism by an α-PFT protein from Vibrio cholerae. As part of the MakA/B/E tripartite toxin, MakA is involved in membrane pore formation similar to other α-PFTs. In contrast, MakA in isolation induces tube-like structures in acidic endosomal compartments of epithelial cells in vitro. The present study unravels the dynamics of tubular growth, which occurs in a pH-, lipid-, and concentration-dependent manner. Within acidified organelle lumens or when incubated with cells in acidic media, MakA forms oligomers and remodels membranes into high-curvature tubes leading to loss of membrane integrity. A 3.7 Å cryo-electron microscopy structure of MakA filaments reveals a unique protein-lipid superstructure. MakA forms a pinecone-like spiral with a central cavity and a thin annular lipid bilayer embedded between the MakA transmembrane helices in its active α-PFT conformation. Our study provides insights into a novel tubulation mechanism of an α-PFT protein and a new mode of action by a secreted bacterial toxin.
Integrated Microscopy Technologies Umeå [Service]
Swedish NMR Centre (SNC) [Collaborative]
PubMed 35131030
DOI 10.7554/eLife.73439
Crossref 10.7554/eLife.73439
pii: 73439
pmc: PMC8824476