Mechanism of membrane binding and disruption by kB1.

(A) The membrane binding mechanism of monomeric kB1. (i) Before the membrane binding process, Trp19 (extended green trapezoid) is exposed to the water. (ii) Membrane binding begins when Trp19 binds to the membrane. (iii) Hydrophobic residues in loop 5 (green patch) then bind to the membrane. (iiii) Next, hydrophobic residues in loops 5 and 6 (pink patch) bind to the hydrophobic region of the membrane while hydrophilic residues in loops 1, 2, 3 and 6 (blue patch) localize to water and the polar head region of the membrane. (B) The membrane binding mechanism of tetrameric kB1. (i) Loop 5 of one kB1 molecule interacts with loop 5 of other kB1 molecules to form a tetramer in the water. (ii) The tetramer cannot bind to the membrane when hydrophilic residues in loops 1, 2, 3 and 6 or hydrophobic residues in loop 6 reach the membrane. (iii) The tetramer binds to the membrane when Trp19 is exposed to water and is proximal to the membrane surface. (iiii) Hydrophobic residues in loop 5 then bind to the membrane. All hydrophobic residues in loop 6 then expand from the center of the tetramer and bind to the membrane. (C) The membrane binding of kB1 as a tower like cluster [29]. (i) Tetramer in the water bind to a monomer that is successfully bound to the membrane. (ii) In the tower-like cluster, the tetramer is held near the membrane surface. (iii) A wall-like cluster [29] is formed. (D) kB1 molecules do not penetrate the membrane but form a channel on the membrane surface and induce positive membrane curvature [29]. (E) At high kB1 concentrations, lipid molecules are extracted from the membrane to the channel inside the kB1 cluster [29]. All panels are shown in side view. Only half of the kB1 channel is shown in (D) and (E). Polar heads of lipids are shown as orange circles while hydrophobic tails are shown as black lines.