Physiological membrane vesicles are built to separate reaction spaces in a stable manner, even when they accidentally collide or are kept in apposition by spatial constraints in the cell. This requires a natural resistance to fusion and mixing of their content, which originates from substantial energetic barriers to membrane fusion [1]. To facilitate intracellular membrane fusion reactions in a controlled manner, proteinaceous fusion machineries have evolved. An important open question is whether protein fusion machineries actively pull the fusion reaction over the present free energy barriers, or whether they rather catalyze fusion by lowering those barriers. At first sight, fusion proteins such as SNARE complexes and viral fusion proteins appear to act as nano-machines, which mechanically transduce force to the membranes and thereby overcome the free energy barriers [2,3]. Whether fusion proteins additionally alter the free energy landscape of the fusion reaction via catalytic roles is less obvious. This is a question that we shall discuss in this review, with particular focus on the influence of the eukaryotic SNARE-dependent fusion machinery on the final step of the reaction, the formation and expansion of the fusion pore.

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