![]() ![]() ![]() elegans protein EFF-1, which is necessary ( Mohler et al., 2002) and sufficient ( Shemer et al., 2004) for most epithelial cell fusion events in the developing worm. A strong candidate for a `true' fusion protein is the C. Whether this is because an alternative fusion mechanism is used for each case of cell-cell fusion or because these particular proteins do not represent the fusion protein, per se, is not yet clear. Putative cell-cell fusion proteins are diverse in structure and few match the portrait of a canonical viral fusion protein. In virus-cell fusion, a fusion protein typically contains a single transmembrane domain and a fusion peptide – a sequence of 10-30 residues that form an amphiphilic domain at the N-terminus (class I) or within the protein (class II) that is crucial for fusion ( Chernomordik and Kozlov, 2003 Jahn et al., 2003). The similarities between cell-cell and viral-cell attachment proteins probably stem from their common function and might provide predictive criteria with which to evaluate candidates as for sperm-egg attachment proteins.įusion proteins directly mediate the mixing of two membrane bilayers. All of these proteins contain cell adhesion domains, and optimal function of the myoblast fusion candidates requires the participation of several proteins. The Caenorhabditis elegans sperm protein SPE-9 contains ten epidermal growth factor (EGF) repeats in its extracellular domain and is likely to act as an attachment factor in gamete fusion ( Singson et al., 1998). Fus1 is a single-pass transmembrane protein sequence that has similarity within five Ig-like repeats to bacterial invasins and intimins, which mediate the adhesion step that precedes bacterial invasion of host cells. In Chlamydomonas, fus1 mutants are unable to attach to the mating process of the opposite mating type and fusion is never observed ( Misamore et al., 2003). Cells expressing Duf aggregate in vitro with cells expressing Sns and Hbs, and it is likely that these proteins function cooperatively in attachment in vivo. Null mutations in the sns or rst and duf gene, or overexpression of hbs, leads to defects in myoblast fusion at the attachment stage. Each of these proteins contains several Ig-like domains, which are well-defined cell-cell adhesion domains. The best-characterized candidates are the four immunoglobulin (Ig)-superfamily members involved in Drosophila myoblast fusion: Sns, Hbs, Duf and Rst ( Taylor, 2002). ![]() Several putative cell-cell attachment proteins share these characteristics. In many cases, multiple proteins participate in a single virus-cell attachment event, producing a complex interaction that occurs in a limited time frame. In virus-cell fusion, virus-receptor interactions are mediated by carbohydrate moieties or cell adhesion domains on proteins or other molecules in the plasma membrane ( Bomsel and Alfsen, 2003 Dimitrov, 2004). Throughout the following discussion, we refer to proteins thought to mediate step one as `attachment' proteins and steps two and three as `fusion' proteins.Īttachment proteins are responsible for the initial interaction between two membranes. In some viral fusion systems, the fusion peptide is thought to actively disrupt the organization of the lipid in the membrane, which facilitates the fusion event ( Tamm et al., 2003). It is not clear whether proteins are necessary for this step, because liposomes can be induced to fuse without proteins. Third, lipid mixing: once membranes are very close, lipid mixing will occur between the proximal membrane leaflets and then the distal leaflets, leading to cytoplasmic continuity between the two cells ( Jahn and Grubmuller, 2002). This shape change results in a hinge-like motion that draws the two membrane-inserted ends of the protein very close together, pulling the membranes with it ( Smith and Helenius, 2004). One of a variety of factors then induces an irreversible conformational change in which the fusion protein folds back on itself. In many systems, this is accomplished by a fusion protein spanning the intermembrane space and physically linking the two membranes (through protein-lipid or protein-protein interactions). Second, membrane apposition: the activity of fusion proteins brings the two membranes even closer together. This step ensures target specificity and is referred to as attachment. First, membrane recognition (attachment): initial membrane contact is achieved through protein-protein-mediated or protein-carbohydrate-mediated binding of the two membranes. The membrane fusion process can be divided into three key events.
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