Mutational analysis of the interaction between CD4 and class II MHC: Class II antigens contact CD4 on a surface opposite the gp120-binding site

Fleury, Sylvain; Lamarre, Daniel; Meloche, Sylvain; Ryu, Seong Eon; Cantin, Claude; Hendrickson, Wayne A.; Sékaly, Rafick Pierre

doi:10.1016/0092-8674(91)90447-7

Cited by 142 publications

(106 citation statements)

References 47 publications

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“…Therefore, mutations of residues predicted to be distant from the E-F loop were made as controls. We choose loops analogous to regions in Ig-fold containing proteins that contribute to protein interactions; the complementarity-determining region CDR2 of immunoglobulins corresponds to the C'-C" loop and both the C-C' and C'-C" loops contribute to the ligand binding sites of T cell surface molecules (Amit et al, 1986;Colman et al, 1987;Sheriff et al, 1987;Driscoll et al, 1991;Fleury et al, 1991;Jones et al, 1992;Leahy et al, 1992). The F-G loop of a-agglutinin domain III, which corresponds to CDR3 of immunoglobulins, is highly glycosylated (Figure 2A; Chen et al, 1995) and therefore unlikely to contribute to ligand binding.…”

Section: Resultsmentioning

confidence: 99%

Identification of a ligand-binding site in an immunoglobulin fold domain of the Saccharomyces cerevisiae adhesion protein alpha-agglutinin.

Nobel

Lipke

Kurjan

1996

MBoC

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The Saccharomyces cerevisiae adhesion protein a-agglutinin (Agalp) is expressed by a cells and binds to the complementary a-agglutinin expressed by a cells. The N-terminal half of a-agglutinin is sufficient for ligand binding and has been proposed to contain an immunoglobulin (Ig) fold domain. Based on a structural homology model for this domain and a previously identified critical residue (His292), we made Agalp mutations in three discontinuous patches of the domain that are predicted to be in close proximity to His292 in the model. Residues in each of the three patches were identified that are important for activity and therefore define a putative ligand binding site, whereas mutations in distant loops had no effect on activity. This putative binding site is on a different surface of the Ig fold than the defined binding sites of immunoglobulins and other members of the Ig superfamily. Comparison of protein interaction sites by structural and mutational analysis has indicated that the area of surface contact is larger than the functional binding site identified by mutagenesis. The putative a-agglutinin binding site is therefore likely to identify residues that contribute to the functional binding site within a larger area that contacts a-agglutinin.

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Section: Resultsmentioning

confidence: 99%

Identification of a ligand-binding site in an immunoglobulin fold domain of the Saccharomyces cerevisiae adhesion protein alpha-agglutinin.

Nobel

Lipke

Kurjan

1996

MBoC

View full text Add to dashboard Cite

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“…L-68 and OKT4 are mouse mAbs specific to human CD4 (12,23). The rabbit anti-human CD4 polyclonal serum was a gift of Dr. A. Truneh (SmithKline Beecham Pharmaceuticals, King of Prussia, PA).…”

Section: Antibodiesmentioning

confidence: 99%

“…After overnight incubation at 37°C, supernatants were then harvested and levels of IL-2 production were assessed using the IL-2-dependent cell line CTLL.2 and the hexosaminidase colorimetric assay as previously described (23).…”

Section: Stimulation Of T Cells and Measurement Of Il-2 Productionmentioning

confidence: 99%

“…3DT52.5.8 is a murine CD4 negative T cell hybridoma obtained by single-cell cloning of 3DT52.5 hybridoma (20 -22). DAP-D d , DAP-D d DR4, and DAP-DR1 were generated by stably transfecting DAP-3 cells (12,23) with the gene encoding the murine MHC class I isotype D d alone or together with cDNAs encoding the ␣-and ␤-chains of the human class II isotypes DR4 or with cDNA encoding the isotype DR1, respectively (12,24).…”

Section: Cellsmentioning

confidence: 99%

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CD4 Dimers Constitute the Functional Component Required for T Cell Activation

Moldovan

Yachou

Lévesque³

et al. 2002

The Journal of Immunology

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The CD4 molecule plays a key role in the development and activation of helper T cells. Dimerization and oligomerization is often a necessary step in the function of several cell surface receptors. Herein, we provide direct biochemical evidence confirming the presence of CD4 as dimers in transfected cells from hemopoetic and fibroblastic origin as well as in primary T cells. Such dimers are also observed with murine CD4 confirming selective pressure during evolution to maintain such a structure. Using a series of point mutations, we have precisely mapped the dimerization site at residues K318 and Q344 within the fourth extracellular domain of CD4. These residues are highly conserved and their mutation results in interference with dimer formation. More importantly, we demonstrate that dimer formation is essential for the coligand and coreceptor functions of CD4 in T cell activation. These data strongly suggest that CD4 dimerization is necessary for helper T cell function.

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“…The formation of the ternary complex is believed to raise the total avidity of the TCR⅐MHC interaction and to trigger cytoplasmic signal transduction by bringing a tyrosine kinase p56lck associated with the cytoplasmic portion of the CD4 into the vicinity of the TCR⅐CD3 complex for phosphorylation of the chain (12)(13)(14). In one series of studies, the ability of mutant CD4 molecules to assist the recognition of class I MHC molecules by class I-restricted TCR was studied (26,27). In this situation, TCR⅐MHC⅐CD4 ternary complexes should not have been formed.…”

Section: Discussionmentioning

confidence: 99%

Coreceptor Function of Mutant Human CD4 Molecules without Affinity to gp120 of Human Immunodeficiency Virus

Tachibana¹,

Siddiqi²,

Ikegami³

et al. 2000

Journal of Biological Chemistry

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Despite extensive mutational studies on the human CD4 molecule and its affinity to human immunodeficiency virus (HIV) envelope glycoprotein gp120, coreceptor functions of such mutant molecules have only been examined by indirect measurement of their affinity to class II major histocompatibility complex (MHC) molecules. In this report, coreceptor functions of mutant human CD4 molecules, which have no or reduced affinity to an HIV envelope protein, gp120, were assessed in a murine T cell receptor/class II MHC recognition system. The substitution of human C؆ ␤ strand with the murine homologous segment resulted in the loss of the coreceptor function as well as in the complete loss of gp120 binding capacity, corroborating the consensus that Phe-43 in C؆ ␤ strand plays crucial roles in both situations. However, simultaneous replacement of the C-C؆ loop along with the C؆ ␤ strand by homologous murine segments rescued the coreceptor function, whereas gp120 binding capacity remained negative. Further analysis indicated that insertion of lysine between Gly-41 and Ser-42 can partially compensate for the coreceptor function lost by the Phe-43 3 Val mutation. Although the coreceptor function of these mutant CD4 molecules in a human T cell recognition system is yet to be determined, these observations necessitate a re-evaluation of the role played by Phe-43 in coreceptor function. Examination of the sensitivities of the mutant CD4 molecules expressed on HeLa cells to infection by a T cell-tropic HIV-1 strain indicated that only those mutants that had completely lost gp120 binding capacity were resistant to the infection. All mutants having whole C؆ substitution, irrespective of additional substitutions or their coreceptor functions, were resistant to the infection.The most serious consequence of the human immunodeficiency virus type 1 (HIV-1) 1 infection is the acquired immunodeficiency syndrome characterized by severe deficiency of CD4 ϩ T cell functions. Such deficiency of CD4 ϩ T cells stems from the affinity of an HIV envelope protein, gp120, to the human CD4 molecule (1). Several etiological mechanisms causing the functional deficiency of CD4 ϩ T cells are involved; 1) targeted infection of CD4 ϩ cells initiated by the binding of the virus to CD4, 2) cell fusion induced by binding of HIV viruses resulting in apoptosis of CD4 ϩ T cells, and 3) inhibition of the specific recognition of antigenic peptide/class II major histocompatibility complexes (MHCs) by soluble gp120. Extensive mutational analyses on the human CD4 molecule have identified a CЈ-CЉ ridge of the D1 domain as the gp120 binding area (2-4). The murine CD4 molecule has no affinity to gp120, although it shares 55% sequence homology of the extracellular portion with its human counterpart. Segmental as well as single amino acid substitutions of the human CD4 molecule with murine sequences confirmed the crucial role played by an aromatic ring of Phe-43 in gp120 binding (5).Several reports have claimed that the loss of gp120 binding ability of the human CD4 molecul...

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Mutational analysis of the interaction between CD4 and class II MHC: Class II antigens contact CD4 on a surface opposite the gp120-binding site

Cited by 142 publications

References 47 publications

Identification of a ligand-binding site in an immunoglobulin fold domain of the Saccharomyces cerevisiae adhesion protein alpha-agglutinin.

Identification of a ligand-binding site in an immunoglobulin fold domain of the Saccharomyces cerevisiae adhesion protein alpha-agglutinin.

CD4 Dimers Constitute the Functional Component Required for T Cell Activation

Coreceptor Function of Mutant Human CD4 Molecules without Affinity to gp120 of Human Immunodeficiency Virus

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