Membrane fusion and exocytosis

Membrane fusion involves the merger of two phospholipid bilayers in an aque ous environment. In artificial lipid bilayers, fusion proceeds by means of defined transition states, including hourglass-shaped intermediates in whic h the proximal leaflets of the fusing membranes are merged whereas the dist al leaflets are separate (fusion stalk), followed by the reversible opening of small aqueous fusion pores. Fusion of biological membranes requires the action of specific fusion proteins. Best understood are the viral fusion p roteins that are responsible for merging the viral with the host cell membr ane during infection. These proteins undergo spontaneous and dramatic confo rmational changes upon activation. In the case of the paradigmatic fusion p roteins of the influenza virus and of the human immunodeficiency virus, an amphiphilic fusion peptide is inserted into the target membrane. The protei n then reorients itself, thus forcing the fusing membranes together and ind ucing lipid mixing. Fusion of intracellular membranes in eukaryotic cells i nvolves several protein families including SNAREs, Rab proteins, and Sec1/M unc-18 related proteins (SM-proteins). SNAREs form a novel superfamily of s mall and mostly membrane-anchored proteins that share a common motif of abo ut 60 amino acids (SNARE motif). SNAREs reversibly assemble into tightly pa cked helical bundles, the core complexes. Assembly is thought to pull the f using membranes closely together, thus inducing fusion. SM-proteins compris e a family of soluble proteins that bind to certain types of SNAREs and pre vent the formation of con complexes. Rab proteins are GTPases that undergo highly regulated GTP-GDP cycles. In their GTP form, they interact with spec ific proteins, the effector proteins. Recent evidence suggests that Rab pro teins function in the initial membrane contact connecting the fusing membra nes but are not involved in the fusion reaction itself.