Abstract Many pathogenic bacteria produce protein toxins that target and perturb host cell membranes. The secreted α-pore-forming toxins (α-PFTs) cause membrane damage via pore formation. This study demonstrates 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 protein alone induces tube-like structures in the acidic lysosomal host cell compartment. In vitro studies unravel the dynamics of tubular growth, which occur in a pH-, lipid- and concentration-dependent manner. A 3.7-Å cryo-electron microscopy structure of MakA filaments reveals a unique protein-lipid superstructure. In its active α-PFT conformation, MakA embeds its transmembrane helices into a thin annular lipid bilayer and spirals around a central cavity. Our study provides molecular insights into a novel tubulation mechanism of an α-PFT protein, revealing a new mode of action by a secreted bacterial toxin.

Protein-lipid interaction at low pH induces oligomerisation of the MakA cytotoxin from Vibrio cholerae