Fusion mechanism

The fusion mechanism describes any mechanism by which cell fusion or virus-cell fusion takes place, as well as the machinery that facilitates these processes. Cell fusion is the formation of a hybrid cell from two separate cells. There are three major actions taken in both virus-cell fusion and cell-cell fusion: '1) dehydrate polar head groups, (2) promote a hemifusion stalk, and (3) open and expand pores between fusing cells.' Virus-cell fusions occur during infections of several viruses that are health concerns relevant today. Some of these include HIV, Ebola, and Influenza. For example HIV infects by fusing with the membranes of immune system cells. In order for HIV to fuse with a cell, it must be able to bind to the receptors CD4, CCR5, and CXCR4. Cell fusion also occurs in a multitude of mammalian cells including gametes and myoblasts. The fusion mechanism describes any mechanism by which cell fusion or virus-cell fusion takes place, as well as the machinery that facilitates these processes. Cell fusion is the formation of a hybrid cell from two separate cells. There are three major actions taken in both virus-cell fusion and cell-cell fusion: '1) dehydrate polar head groups, (2) promote a hemifusion stalk, and (3) open and expand pores between fusing cells.' Virus-cell fusions occur during infections of several viruses that are health concerns relevant today. Some of these include HIV, Ebola, and Influenza. For example HIV infects by fusing with the membranes of immune system cells. In order for HIV to fuse with a cell, it must be able to bind to the receptors CD4, CCR5, and CXCR4. Cell fusion also occurs in a multitude of mammalian cells including gametes and myoblasts. Proteins that allow viral or cell membranes to overcome barriers to fusion are called fusogens. Fusogens involved in virus to cell fusion mechanisms were the first of these proteins to be discovered. Viral fusion proteins are necessary for membrane fusion to take place. There is evidence that ancestral species of mammals may have incorporated these same proteins into their own cells as a result of infection. For this reason, similar mechanisms and machinery are utilized in cell-cell fusion. In response to certain stimuli, such as low pH or binding to cellular receptors, these fusogens will change conformation. The conformation change allows the exposure of hydrophobic regions of the fusogens that would normally be hidden internally due to energetically unfavorable interactions with the cytosol or extracellular fluid. These hydrophobic regions are known as fusion peptides or fusion loops, and they are responsible for causing localized membrane instability and fusion. Scientists have found the following four classes of fusogens to be involved with virus-cell or cell-cell fusions. These fusogens are trimeric, meaning they are made of three subunits. Their fusion loops are hidden internally at the junctions of the monomers before fusion takes place. Once fusion is complete, they refold into a different trimeric structure than the structure they had before fusion. These fusogens are characterized by a group of six α-helices in their post-fusion structure. This class of fusogens contains some of the proteins utilized by influenza, HIV, and Ebola during infection. This class of fusogens also includes syncytins which are utilized in mammalian cell fusions. In contrast to Class I fusogens, Class II fusogens contain multiple β-pleated sheets. These proteins are also trimeric and take part in the insertion of fusion loops into the target membrane. Their conformation changes are a result of exposure to acidic environments. Class III fusogens are involved with virus-cell fusions. Much like fusogens in the previous two classes, these proteins are trimeric. However, they contain both α-helices and β-pleated sheets. During cell fusion the monomers of these proteins will dissociate but will return to a different trimeric structure after the fusion is complete. They are also involved in the insertion of fusion loops in the membrane. These reoviral cell-cell fusogens contain fusion loops that can induce cell fusion. They form polymeric structures to induce fusion of membranes. Reoviruses do not have membranes themselves, so class IV fusogens are not usually involved in traditional virus-cell fusion. However, when they are expressed on the surface of cells, they can induce cell-cell fusion. The fusogens of classes I-III have many structural differences. However, the method they utilize to induce membrane fusion is mechanistically similar. When activated, all of these fusogens form elongated trimeric structures and bury their fusion peptides into the membrane of the target cell. They are secured in the viral membrane by hydrophobic trans-membrane regions. These fusogens will then fold in on themselves forming a structure that is reminiscent of a hairpin. This folding action brings the transmembrane region and the fusion loop adjacent to each other. Consequently, the viral membrane and the target cell membrane are also pulled close together. As the membranes are brought closer together, they are dehydrated which allows the membranes to be brought into contact. Interactions between hydrophobic amino-acid residues and the adjacent membranes cause destabilization of the membranes. This allows the phospholipids in the outer layer of each membrane to interact with each other. The outer leaflets of the two membranes form a hemifusion stalk to minimize energetically unfavorable interactions between hydrophobic phospholipid tails and the environment. This stalk expands, allowing the inner leaflets of each membrane to interact. These inner leaflets then fuse, forming a fusion pore. At this point, the cytoplasmic components of the cell and the virus begin to mix. As the fusion pore expands, virus-cell fusion is completed. Though there is much variation in different fusions between mammalian cells, there are five stages that occur in a majority of these fusion events: 'programming fusion-competent status, chemotaxis, membrane adhesion, membrane fusion, and post-fusion resetting.'