Introduction
CD4 is a cellular immune response co-receptor that raises the avidity of relationship between an antigen-presenting cell and a T-cell through interaction with non-polymorphic parts of the complex between T-cell receptor and major histocompatibility class II molecules. It directly contributes to transduction of signal via cytoplasmic relationship with the lymphocyte kinase. CD4 also plays a role as the high-affinity receptor for attachment of cells as well as entrance of HIV. The CD4 extracellular part consists of domains that resemble immunoglobulin D1 to D4. This component of the CD4 has been qualified as a recombinant soluble protein, and crystal structures have been identified for D1D2 fragment of human.
These structures possess a hinge-like inconsistency at the junction between D1D2 and D3D4, which may be essential in fusion of HIV and immune recognition. They are also important in a usual dimeric relationship through D4 domains. Measurements of dynamic light scattering together with chemical cross-linking of corroborate dimerization of CD4 at high concentrations of protein. Such dimmers can be relevant as signal transduction mediators in T cells (Wu, Kwong, & Hendrickson, 1997).
The HIV entry into host cells is arbitrated by the glycoproteins of the viral envelope that are classified into oligomeric, almost certainly trimeric spikes exhibited on the virion’s surface. These complexes of the envelope are grounded in the membrane of the virus using envelope glycoprotein, gp41 transmembrane. The spike surface basically consists of the outer envelope glycoprotein, gp120, connected through non-covalent interactions with every trimeric gp41 glycoprotein complex subunit (Lu, Blackslow, & Kim, 1995). Comparing the sequences of gp120 in different primate immunodeficiency viruses keyed out five variable areas, V1–V5. The first four variable areas make loops that are surface-exposed and comprise disulphide bonds at their bases.
Binding of CD4 stimulates conformational alterations in the glycoprotein gp120, some of which engage in contact and formation of a site for binding for specific chemokine receptors.These receptors, mostly CXCR4 and CCR5 for HIV-1, act as virus entry’s obligate second receptors. The third variable loop for gp120 is the main determinant of specificity of chemokine receptor (Wyatt, et al., 1998).
Binding of CD4 may activate extra conformational changes in the glycoproteins of the envelope. For instance, CD4 binding to the envelope glycoproteins of a number of HIV-1 isolates activates the liberation of gp120 from the complex 21, even though the relevance of this procedure to entry of HIV is not certain.
Structure features
CD4 comprises of a total of 428 amino acids, which are circulated into segments as below, extracellular segment of 372 amino acids, transmembrane segment of 23 amino acids, as well as a cytoplasmic segment of 33 amino acids (Wu, 1996). The extracellular area of the CD4 protein is a sole chain molecule, which is comprised of four immunoglobulin-like domains that have a tandem arrangement. These domains are categorized by their connection to the membrane such that there is a segment of two domains known as the membrane distal fragment (Wu, 1996). The domain D1 is the domain of interest with regard to HIV and the gp120 protein. This domain is homologous to the antibodies variable domain that shows the structure of two Beta sheets that are four or five strands long (Wu, 1996). The D1stucture is steady with that of V-Domain while D2 and D4 are classified as C-Domains. The variable domain is frequently accompanied by a connecting region (Wu, 1996).
The adaptive immune response relies on the particular recognition of the antigenic peptide that is attached a molecule of histocompatibility complex (MHC) known as pMHC. It also relies on the interaction of the same pMHC with coreceptors of CD4 orCD8.
Function
The CD4 cell has tandem extracellular domains namely, D1, D2, D3, and D4. In a normal organism that is virus free, these termini are utilized by CD4 for recognition of antigen while connected with extracellular class II major histocompatibility complex (Wu, 1996). In previous studies, it has been demonstrated that CD4 is the most important site for binding the T4/leu3 antigen (Wu, 1996). Even though, this reaction happens outside cell, CD4 may as well go through reactions inside cells with the src-like lymphocyte tyrosine kinase. While looking at the T4/leu3structure, the antigen comprises of a V-J Domain area, which is homologous to the major histocompatibility complex class II complex (Wu, 1996). This means that the antigen’s structure is of importance so that it can be recognized by CD4. The V-J style domain being recognized by CD4's D1 V-J Domain, it is easy to understand how CD4 binds to gp120.
The primary site for the bonding of CD4 to gp120 takes place at the terminus of D1 domain, which possesses a V-J Domain structure. Even though, the gp120structure is variable, CD4 protein recognizes its structure, and there occurs an electrostatic bond between the two. The HIV puts in its DNA into the T-Cell from this bond and leads to the serious problems related to the disease. The protein structure is the most important aspect of this bond. When the D1 domain of CD4 is manipulated in a number of ways to find out if the structure that would result would have an impact on the rate at which CD4 would bind to gp120. As predictions were, changing the domain’s shape, the rate at which CD4 bind to gp120 changed 50 times in a number of occurrences while others changed 200times (Wu, 1996). Even though, the precise interaction between these two proteins is still not known, it has been found out that the CD4 protein structure is very much an essential aspect in its capability to bind with gp120 (Wu, 1996).
Methods and result
In an experiment, two strategies were employed to key out sites of interaction between class II major histocompatibility complex and the receptor of CD4. Due to the fact that CDA of mouse does not interact well with the molecules of human major histocompatibility complex class II but human CD4 interacts well with the class II molecules of mouse, the mouse MHC class II species-conserved residues were substituted with the comparable to human residues. Due to the homologies of structure as well as similar roles of molecules of major histocompatibility complex class I and II, there was anticipation that CD4 may have an interaction with class II at a site that is analogous to the CD8-binding site.
Thus, mutations of class II in the area corresponding to 223-229 residues of class I domain were assessed for loss of interaction. Aβd mutated complementary DNAs were cotransfected, in mouse L cells, with wild type Aαd. Molecules of class II exhibiting undiminished reactivity with the three antibodies were examined for interaction with CD4 by use of a functional assay entailing activation of T cell by either Staphylococcal enterotoxin or peptide antigen. Hybridomas of T cell with a variety of αβ antigen receptors and showing a number of co receptor molecules were utilized. They all released lymphokine following engagement of receptor by class II related ligands. However, in the presence of an efficient major histocompatibility complex class II-CD4 interaction, the threshold of antigen is lower while the production of lymphokine at a given concentration of antigen is higher. The results keyed out the β2 domain region between 137-143 residues as fundamental determinants of interaction of class II with CD4.
Discussion
Asparagine substitution at location 110 of Aβu with glutamine, the residue taking place in many human alleles at this location partially lowered the co receptor role of murine CD4. It, however, exhibited no impact on the reactions of human CD4 expressing hybridomas. Thus, this residue most likely takes part in the murine CD4 and human class II impaired interaction (Konig, Huang, & Germain, 1992).
Conclusion
The crystal structure of CD4-pMHCII argues for a V-shaped ternary complex of CD4 –pMHCII–TCR as the basis of activation of helper T-cell. It also shows that gp120 binds to the same structural CD4 elements used by pMHCII, and to additional sites.
Therefore, the virus has gone through evolution to imitate the normal interaction between pMHCII and CD4. In this way, the protein of the virus usurps the normal CD4-pMHCII binding essential for the function of helper T-cell, thus leading to the human immuno-deficiency (Wang, et al., 2001).
Reference Lists
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