Fig. 4.

Potential homotypic and heterotypic TMD interactions in the function of S²¹. (A) Helical projections of TMDs of S²¹. Stars indicate GxxxGxxxG-like motifs of each TMD (G10, G14, and G18 in TMD1; G40, S44, and G48 in TMD2). Hydrophilic or neutral residues in each TMD are circled and shaded. (Left) the SAR domain (TMD1) of S²¹ (residues 7–27), with the position of the S16C mutation highlighted by an asterisk. (Right) TMD2, the hole-forming domain of S²¹ (residues 36–60), with a potential hydrophilic surface that may line the lethal membrane lesion indicated by the arc. (B) Pathway to hole formation involves inhibited (i) and active (ii) topological isomers of S²¹. See Discussion for details.