Chapter 6 Membrane fusion and exocytosis

Abstract

Summary The lipid bilayer membranes that separate cells and organelles undergo fusion to permit the exchange or compartmentalization of macromolecules. The fusion events involve contact between cytoplasmic or between extracytoplasmic membrane surfaces. These two types of fusion may depend on very different mechanisms because of the different environments of the membrane surfaces. The membrane fusion process can be broken down into the following steps: (1) translocation, the positioning of membranes adjacent to one another, (2) recognition, initial specific interaction between the appropriate fusion partners, (3) attachment, a close physical sealing between the two bilayers, (4) disruption, alteration of bilayer structure to create an aqueous passageway through the membranes, (5) reorganization, the formation of new bilayer(s) from the disrupted membrane components. Any or all of these steps may be mediated by specific proteins and be subject to regulation. The secretory pathway includes a number of steps that involve membrane fusion: pinching off and fusing of transport vesicles in the endoplasmic reticulum and the Golgi pinching off of secretory vesicles from the Golgi; fusion of secretory vesicles with the plasma membrane during simple exocytosis or with one another during compound exocytosis, and pinching off of endocytic vesicles to recycle secretory vesicle membrane. The molecular basis of these events has been studied using several important model systems that can be subjected to biochemical or genetic analyses. These include the constitutive secretory pathway of yeast, the regulated secretory pathway of the endocrine chromaffin cell, and the action of Clostridial neurotoxins on synaptic transmission. A group of yeast genes (the SEC genes) have been identified that mediate several steps in the secretory pathway. These genes have mammalian counterparts that may play similar roles. The annexins are a group of calcium-dependent, lipid-binding proteins that might mediate the binding of the secretory vesicle to the plasma membrane during regulated secretion. Protein components of the secretory vesicle or plasma membrane that may function in exocytosis are targets for the proteolytic activities of neurotoxins that block exocytosis. These membrane proteins include synaptobrevin, syntaxin, and SNAP25. Genetic analysis of lower eukaryotes indicates another secretory vesicle membrane protein, synaptotagmin, may provide regulation of the exocytosis complex of proteins in response to changes in the intracellular calcium concentration. These newly described protein mediators of membrane fusion in exocytosis are promising targets for the development of novel pharmacological agents to manipulate hormone or neurotransmitter release.