The local detergent model of SNARE-mediated membrane fusion

ABSTRACT Models of membrane fusion generally assume that strong repulsion between membranes hinders fusion and use macroscopic properties to describe how proteins induce fusion of membranes. Soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) are commonly believed to mediate intracellular membrane fusion by forming continuous α-helices that assemble into stable complexes, acting as semi-rigid rods that overcome the repulsion between the membranes, bending and squeezing them to cause fusion. However, some evidence indicates that membranes can readily be brought into contact and that helix continuity is not necessary for SNARE function. This Hypothesis article reviews recent molecular dynamics simulations that suggested a fundamentally different model, which postulates that the key obstacle to initiating fusion is the difficulty of mixing the hydrophobic interiors of the two membranes at the polar membrane-membrane interface and that SNAREs act as local detergents to catalyze such mixing. The SNAREs also facilitate evolution of the resulting hydrophobic core into a series of asymmetric stalk-like structures and formation of the fusion pore. The structural properties of cell–cell and virus–cell fusion proteins indicate that they all can act as local detergents; therefore, this central aspect of SNARE function could be universal for all types of biological membrane fusion.