1.C.41.1.4
MakABE tricomponent cytotoxin.  Tetrameric MakA cytotoxin of 369 aas and 2 or 3 TMSs in a 1 (moderately hydrophobic, N-terminal) + 2 TMS (central, very hydrophobic) arrangement. The protein-lipid interactions at low pH induce oligomerization of the MakA cytotoxin (Nadeem et al. 2022). The alpha-pore-forming toxins (α-PFTs) from pathogenic bacteria damage host cell membranes by pore formation. Nadeem et al. 2022 demonstrated the mechanism of MakA/B/E tripartite toxin, MakA is involved in membrane pore formation similar to other α-PFTs. In contrast, MakA in isolation forms tube-like structures in acidic endosomal compartments of epithelial cells in vitro. Nadeem et al. 2022 unraveled 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-EM structure of MakA filaments (7P3RA-D) revealed 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 alpha-PFT conformation. MakB of 355 aas and possibly 2 central TMSs is a motility-associated killer factor (6W1W_A,B; 6TAO_A,B). MakA and MakB appear to be distantly related to each other (~20% identical over most of their lengths).  MakE was not found in the NCBI database. V. cholerae MakA is a cholesterol-binding pore-forming toxin that induces non-canonical autophagy (Jia et al. 2022). Protein-lipid interactions at low pH induces oligomerization of the MakA cytotoxin from Vibrio cholerae (Nadeem et al. 2022).