How could SNARE proteins open a fusion pore?

Abstract

The SNARE (Soluble NSF Attachment protein REceptor) complex, which in mammalian neurosecretory cells is composed of the proteins synaptobrevin 2 (also called VAMP2), syntaxin, and SNAP-25, plays a key role in vesicle fusion. In this review, we discuss the hypothesis that, in neurosecretory cells, fusion pore formation is directly accomplished by a conformational change in the SNARE complex via movement of the transmembrane domains.

FIGURE 1.

Structure of the SNARE complex A: hypothetical model for the structure of the trans SNARE complex as suggested by Ref. . The TM domains (yellow) and the SNAP-25 linker (brown) were not part of the crystal structure. B: structure of the post fusion cis SNARE complex, including the TM domains of syb2 and stx, shows helical extension of the SNARE domains into the membrane (56). Figure adapted from Refs. and and used with permission from Nature.

FIGURE 2.

Energetics of syb2 tilting movement in the membrane Harmonic potentials were applied to S115/T116 (ST group) in state (A), generating directional movement through the hydrophobic core (B) to the extravesicular membrane-water interface (C). D: the change of the ST group position is accompanied by a corresponding change of the TM domain tilt angle. E: the free energy profile shows a maximum when the COOH terminus is located near the membrane center (black dots with error bars). The energy barrier is lowered to ∼3 k_BT when an 80-pN force is applied in z direction (broken line). Image adapted from Ref. and used with permission.

FIGURE 3.

Model of TM domain movements Model of TM domain movements leading to fusion pore formation (A) and corresponding states of the syb2 TM domain from CG-MD simulations (35). The zippering of the SNARE complex will lead to helical extension, leading to force transfer and TM domain, tilt as indicated in states i–iv. Fusion pore formation (state vi) could proceed via the stalk state (state v) or could be induced via the transition from state iii to iv. Image adapted from Ref. and used with permission.