Welcome to the Chime Tutorial of the Human T-Cell Glycoprotein CD4. My previous websites have outlined both the Structure and Function as well as the many Orthologs of the CD4 protein. The purpose of this tutorial is to help illustrate and clarify the relationship between the CD4 protein's structure and function.

This Chime website will allow you to manipulate and view the structure, and structural components, of the CD4 protein. Below you will find details about the different structures of the protein and how they can effect the function of the protein. If at any time you wish to reset the view of CD4 please Click Here.

To start, lets review how the CD4 protein functions in the cell. If you recall from my first web page, the CD4 protein is a T-Cell glycoprotein that, under normal circumstances, uses its extracellular domains for antigen recognition when associated with extracellular major histocompatibility complex class II (MHC class II): specificaly the antigen T4/leu3. The MHC class II antigen is mainly found on antigen presenting cells, called APC's (such as B-cells and Macrophages), whose main function is to destroy foreign proteins. The interactions between these cells and the T-helper cells (through the interactions of the MHC class II and CD4 protein) is important in keeping our immune systems free from foreign invaders. Go ahead and Click here to view the structure of the CD4 protein.The domain that is utilized for extracellular binding/recognition of the class II MHC is notably called D1(Green) while the intracellular Domain is called D2 (Blue). So where now does the MHC class II antigen bind to CD4? In previous experiments, scientists have concluded that the bond between the antigen and the protein seem to be very weak, so the exact location is not certain. However through multiple experiments, researchers are confident that the two Domain 1 residues Ser 19 as well as Glu 89 ,and the upper Domain 2 residue Gln 165 , all play an integral part in this reaction.

Now one of the main reasons for studying the T-Cell glycoprotein known as CD4, is its contribution to the contraction of HIV. Scientists have concluded that the CD4 protein is the direct binding site for the HIV gp120. Through previous experiments scientists have determined that the locations known as CDR1 (residues 17-28), CDR2 (residues 42-49), and CDR3 (residues 86-97) together form a complemetary receptor site for both MHC class II and gp120. Previous studies have shown that CDR1 (Cyan) , CDR2 (Yellow), and CDR3 (Magenta) , are such an integral part of the binding of MHC class II and gp120, that mutations in these locations can seriously reduce binding.

So are all of these sites equally important in gp120 binding? Or do each of the domains play a specific role in the binding of the two proteins? Well to start, it seems the positively charged Lys 22 of CDR1, binds directly to the gp120's residue #26. Although this bond is important, it seems that most of the evidence supports that the most integral component of CD4 lies in CDR2. CDR2 contains a loop like structure that is composed of a phenylalanine 43 and an aromatic ring (Yellow) . The Phe 43 ring complex makes direct contact with the gp120 protein, allowing it to bind to the CD4 protein. Scientists have located other prime locations for gp120 binding at residue positions 43-55 (Magenta) . In this area even one single substitution can cause a severe decrease in binding.

As mentioned above when talking about CDR1, it seems that charge of the amino acids that make up the CD4 protein have a impact on the binding between the protein and gp120. Lets take a look at Lys 29 (Orange), 35 (Pink), 49 (Red) and Arg 59 (Cyan) . These proteins are all positively charged amino acids and located near the Phe 43 aromatic ring. These five amino acids are what allows the gp120 of the HIV Virus to attach itself to the CD4 protein and infect the housing T-cells. In previous studies it has been shown that these five residues working together is the most important aspect for the sucessfull binding of gp120 and CD4.

This concludes our chime tutorial, during which I hope I was able to furthure illustrate how the structure of CD4 is vital to the function of the glycoprotein. If you would like to reset the chime model to the original, please Click Here.

References:

Arthos J, Deen FA, Chaikin MA, Fornwald JA, Sathe G, Sattentau QJ, Clapham PR, Weiss SJ, Pietropaolo RA, Truneh A, Maddon PJ, Sweet RW. 1989 May, Indentification of the Residues In Human CD4 Critical for the Binding of HIV [abstract]. In Cell 57:469-481. PubMed Database <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2541915&dopt=Abstract> Accessed 2003 March 12.

Camerini D, Seed B. 1990 March, A CD4 Domain Important for HIV-Mediated Synytium Formation Lies outside the Virus Binding Site [abstract]. In Cell 60:747-754. PubMed Database <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2107024&dopt=Abstract>. Accessed 2003 March 12.

Maddon PJ, Dalgleish A, McDougal JS, Clapham PR, Weiss RA, Axel R. 1986 November. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain [abstract]. In Cell 47:333-348. PubMed Database <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3094962&dopt=Abstract>. Accessed 2003 March 12.

Wu, H., Myszka, D. G., Tendian, S. W., Brouillette, C. G., Sweet, R. W., Chaiken, I. M., Hendrickson, W. A.: Kinetic and structural analysis of mutant CD4 receptors that are defective in HIV gp120 binding. Proc Natl Acad Sci U S A 93 pp. 15030 (1996).

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