Membrane fusion: Kinetics and mechanisms

Abstract

Membrane fusion is an essential process of biological cell function and is presumably mediated by specific membrane proteins. Nevertheless, the final step is the rearrangement of the molecular packing of the lipid molecules in the two apposed membranes to form a single, unified membrane. Recent work on the fusion of phospholipid vesicles, or liposomes, has provided both molecular descriptions of their fusion mechanisms and, of equal importance, a methodology for obtaining the same depth of knowledge for biological membranes. In this review, we describe the current status of liposomal fusion mechanisms, the effect of cellular cytoplasmic agents (proteins, polypeptides and polyamines) on their fusion and (as the best understood biological system) the fusion of viruses with membranes. To the extent possible, we describe both the aggregation kinetics (where the membranes overcome the physical forces opposing their close approach, e.g., electrostatic and hydration) and the fusion kinetics (where the destabilization of the apposed membranes can lead to either fusion or lysis). We also discuss the thermodynamic phases of lipids which sometimes govern the interaction between two liposomes. For phospholipid vesicles we have been able to identify two canonical fusion mechanisms and examples of both mechanisms where the intermembrane intermediates which cause fusion appear to be sufficiently long lived to be examined structurally. We believe that accounting for both the kinetic stages of fusion (i.e., the rate limiting step) and the structural analysis of fusion intermediates will be crucial for elucidating the molecular mechanisms of biological membrane fusion.