HIV-1 gp120 with gp41 Interactive Region
By Martin Richard
HIV-1 gp120 with the gp41-interactive region is the protein of focus in this study (PDB ID: 3JWD). This protein is classified under the category of Viral Proteins. The function of the HIV (Human immunodeficiency virus) is to infect host cells and deplete T-helper cells, which are very important for antibody production and immunity from infection (4). Viral proteins are proteins that are associated with viruses and assist them in the function of the virus. There are many other virus proteins, but specifically, glycoproteins such as the surface glycoprotein gp120 and trans-membrane glycoprotein gp41 play important roles in cell-cell interactions (3). Glycoproteins contain oligosaccharide chains (glycans) that are attached to polypeptides; they are often integral membrane proteins (6). Gp120 and gp41 play an important role in mediating the process of HIV viral infection. Gp120 is an envelope glycoprotein that is exposed on the surface of the HIV virus and gp41 is a trans-membrane protein complex of HIV (1). The mechanism through which a HIV virus infects a cell is through the interaction of three gp120s bound to gp41, which forms an envelope spike that plays a part in the virus-cell attachment (5). Human Immunodeficiency Virus uses its envelope spike to bind to various cell surface receptors, especially CD4 receptors on T-helper cells, and infects them (5) (refer to Figure 1).
The mechanism of HIV-1 gp120 interaction with gp41 should be studied because HIV is a virus that causes acquired immunodeficiency syndrome (AIDS), which is a major disease in human society today that kills a vast amount of people. The interaction between gp120 and gp41 enables the virus to enter a host cell and infect it. AIDS is a disease which breaks down the body’s immune system and leaves people unable to fight off infections; thus, other illnesses are more easily able to infect people and lead to death (6). Upon a search for conserved domains, the results indicated that only conserved regions were the gp120 superfamily. As already mentioned, glycoproteins are important in cell–cell interactions and in the HIV virus, the gp120 glycoprotein interacts with gp41 and together, they interact with CD4 receptors to gain access to the host cells (1). The pathway that the HIV molecule follows is as follows: first the virus finds a target cell, then the envelope protein gp120 binds to CD4 receptors, which triggers the trans-membrane protein gp41 to initiate membrane fusion and allowing the contents of the virus to enter the cell (2). There is a layered architecture of the gp120 and gp41, which provides for conformational diversity used in immune evasion. Also the layered gp120 structure allows movement among alternative glycoprotein conformations which is necessary for virus entry into host cells (5).
The HIV-1 gp120 protein with gp41-interactive region is comprised of 4 distinct polymers, with a total amino acid count of 996 amino acids (5). It is classified under the category of a viral protein and it contains 4 polymeric chains. The first polymer, called Chain A, is 379 residues in length and is 14% helical and 33% beta sheet in composition. This polymer forms the HIV-1 Gp120 Envelope Glycoprotein and contains 6 helices, 31 beta sheets, and also contains the N anc C terminals. The second polymer, calledChain C, is 184 residues in length and is 4% helical and 48% beta sheet in composition. This polymer forms the T-cell surface glycoprotein CD4 protein and contains 2 helices and 19 beta sheets. The third polymer, called Chain L, is 213 residues in length and is 1% helical and 46% beta sheet in composition. This polymer forms the FAB 48D Light Chain and contains 1 helix and 23 beta sheets. The fourth polymer, called Chain H, is 220 residues in length and is 4% helical and 49% beta sheet in composition. This polymer forms the FAB 48D Heavy Chain and contains 3 helices and 23 beta sheets (refer to Figure 2) (5).
Receptor binding by gp120 triggers a series of conformational changes in gp41. The structure of the protein is composed such that some gp120 regions are situated close to the gp41 region in such a way that they form a 7-stranded beta-sandwich (refer to Figure 3). The sandwich structure includes three loop excursions which are attached to highly glycosylated gp120 outer domains. The sandwich structure includes three loop excursions which are attached to highly glycosylated gp120 outer domains. There is a layered architecture of the gp120 and gp41, which provides for conformational diversity used in immune evasion. Also the layered gp120 structure allows movement among alternative glycoprotein conformations which is necessary for virus entry into host cells (refer to Figure 3) (5).
When gp120 binds to the CD4 receptor, a set of conformational changes occur in gp41 causing the virus to fuse to the target cell membrane (5). The glycoproteins, gp120 and gp41, are not linked by disulfide bonds, but are rather held together by non-covalent forces. This allows flexibility for conformation change while still maintaining the overall association between the gp120 and gp41 groups. The anchor that holds gp120 in the viral spike is composed of the 7-stranded β-sandwich. Moreover, the beta-sandwich holds the gp41 in place while allowing gp120 to undergo conformational changes and outer domain movement (5). Furthermore, the β-sandwich region contains a significantly greater amount of hydrogen bonds and hydrophobic interactions compared to the other structurally plastic layers such as gp120; therefore, the β-sandwich remains mostly invariant. Additionally, the possibility of various conformations of gp120 enables it to aid the HIV in immune evasion by hiding the sites of CD4 attachment (5).