Atomic structure of a fragment of human CD4 containing two immunoglobulin-like domains

Wang, Jia-Huai; Yan, Yong-Bin; Garrett, T.P.J.; Wang, Jinhuan; Rodgers, David W.; Garlick, Robert; Tarr, George E.; Husain, Yasmin; Reinherz, Ellis L.; Harrison, Stephen C.

doi:10.1038/348411a0

Cited by 544 publications

(303 citation statements)

References 62 publications

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“…A mutant in this region did not affect binding to sCD200. The alternative possibility that the predicted strands are assigned incorrectly is unlikely as they have many of the characteristic residues for example in beta strands B, C and F. Secondly there is little sequence between the two domains suggesting that the domains may be closely linked as found in CD4 domains 1 to 2 and 3 to 4 [16][17][18], respectively, resulting in a relatively rigid protein.…”

Section: Discussionmentioning

confidence: 99%

The CD200 and CD200 receptor cell surface proteins interact through their N‐terminal immunoglobulin‐like domains

Hatherley

Barclay

2004

Eur J Immunol

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CD200 (OX2) is a broadly distributed cell surface glycoprotein that interacts with a receptor on myeloid cells (CD200R) involved in regulation of macrophage function. Both CD200 and CD200R contain two Ig superfamily domains like many other leukocyte membrane proteins. Site‐directed mutagenesis of CD200R showed that, like CD200, it interacted through its N‐terminal domain. This indicated that the cell‐cell interaction spans four Ig superfamily domains and this distance is similar to many interactions found between T cells and antigen‐presenting cells. This suggests that this topology is also important in interactions of CD200 on a variety of cells with CD200R on myeloid cells, and comparable contact sites may be important mediating regulation in other cell‐cell interactions. The mutagenesis showed that the binding involved the predicted GFCC′ face of its N‐terminal domain, like that of CD200, suggesting that the interaction evolved from a homotypic interaction.

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Section: Discussionmentioning

confidence: 99%

The CD200 and CD200 receptor cell surface proteins interact through their N‐terminal immunoglobulin‐like domains

Hatherley

Barclay

2004

Eur J Immunol

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“…After completion of this work, two reports on the crystallization of the outer two domains of CD4 were published (41,42) . In this very exciting work, the Ig-like structure of both domains was established.…”

Section: Discussionmentioning

confidence: 99%

Mutations in CD8 that affect interactions with HLA class I and monoclonal anti-CD8 antibodies.

Sanders

Fox

Kavathas

1991

The Journal of Experimental Medicine

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SummaryThe T cell co-receptor, CD8, binds to the 0 domain of HLA class I (Salter, R .D., R .J. Benjamin, P.K . Wesley, S .E. Buxton, T.P.J . Garrett, C. Clayberger, A.M . Krensky, A .M . Norman, D.R. Littman, and P Parham . 1990. Nature (Lond]. 345 :41; Connolly, J.M ., TA. Potter, E.M. Wormstall, and TH . Hansen. 1988 . J. ExpL Med. 168 :325 ; and Potter, TA., TV. Rajan, R.F. Dick II, and J .A . Bluestone . 1989 . Natur e (Lond.j. 337 :73). To identify regions of CD8 that are important for binding to HLA class I, we performed a mutational analysis of the CD8 molecule in the immunoglobulin (1g)-like variable domain. Our mutational analysis was based on our finding that using a cell-cell adhesion assay murine CD8 (Lyt-2) did not bind to human class I . Since the interaction of human CD8 with HLA class I is species specific, we substituted nonconservative amino acids from mouse CD8 and analyzed the ability of the mutated CD8 molecules expressed in COS 7 cells to bind HLA class I-bearing B lymphoblastoid cells, UC. Mutants with the greatest effect on binding were located in a portion of the molecule homologous to the first and second hypervariable regions of an antibody combining site. In addition, a panel of 12 anti-CD8 monoclonal antibodies were used to stain the 10 CD8 mutants, and amino acids that affected antibody binding were localized on the crystal structure of the BenceJones homodimer, REI . Support for an Ig-like structure of CD8 can be found in the pattern of substitutions affecting antibody binding. This work supports the similar tertiary structure of the CD8 a-terminal domain and an Ig variable domain.T he TCR-CD3 complex associates with CD8 or CD4 to form a multimeric complex interacting with peptide and HLA class I or HLA class II, respectively, during T cell activation . In addition to their function as adhesion molecules, CD8 and CD4 also serve as signalling molecules. The cytoplasmic domains of CD4 and CDSa bind to the NH2-terminal domain of the intracellular tyrosine protein kinase p56kk (1-3) . Antibody crosslinking of CD8 and CD4 to the TCR-CD3 complex leads to enhanced calcium flux and phosphorylation of a set of proteins, which includes the r chain of the TCR complex (4-6) . The ability of CD8 to induce these changes is dependent on its ability to associate with p56kk . CD8 and CD4 are also important for positive and negative selection in the thymus (7, 8). TCR specificity in T cell repertoire selection is determined by both the TCRa/(3 heterodimer and CD4 or CD8 accessory molecules (9, 10) .The human CD8 molecule is expressed either as an al a homodimer or as an a/(3 heterodimer. The homodimer is expressed exclusively on subsets of TCR-y/S cells and NK cells, and is co-expressed with CD80 on peripheral T cells and thymocytes . Individual human peripheral T cells can express varying amounts of CD8 a/a and alai complexes, and these appear to be differentially regulated upon T cell activation (11). CD8 expression can be induced on human CD4 cells upon activation with mitogens (12) and on murin...

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“…The gp120 glycoprotein binds to the most amino-terminal of the four immunoglobulin-like domains of CD4. Structures of both the N-terminal two domains 8,9 and the entire extracellular portion of CD4 (ref. 10 ) have been determined, and mutagenesis indicates that the CD4 structure analogous to the second complementarity-determining region (CDR2) of immunoglobulins is critical for gp120 binding 11,12 .…”

Section: Author Manuscript Author Manuscriptmentioning

confidence: 99%

Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody

Kwong

Wyatt

Robinson

et al. 1998

Nature

2,731

108

3,142

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The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. These interactions initiate a fusion of the viral and cellular membranes. Although gpl20 can elicit virus-neutralizing antibodies, HIV eludes the immune system. We have solved the X-ray crystal structure at 2.5 Å resolution of an HIV-1 gp120 core complexed with a two-domain fragment of human CD4 and an antigen-binding fragment of a neutralizing antibody that blocks chemokine-receptor binding. The structure reveals a cavity-laden CD4-gp120 interface, a conserved binding site for the chemokine receptor, evidence for a conformational change upon CD4 binding, the nature of a CD4-induced antibody epitope, and specific mechanisms for immune evasion. Our results provide a framework for understanding the complex biology of HIV entry into cells and should guide efforts to intervene.The human immunodeficiency viruses HIV-1 and HIV-2 and the related simian immunodeficiency viruses (SIV) cause the destruction of CD4 + lymphocytes in their respective hosts, resulting in the development of acquired immunodeficiency syndromeCorrespondence and requests for materials should be addressed to W. A.H. (wayne@convex.hhmi.columbia.edu).Coordinates have been deposited in the Brookhaven Protein Data Bank (accession code 1gc1) and maybe obtained from the authors. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript (AIDS) 1,2 . The entry of HIV into host cells is mediated by the viral envelope glycoproteins, which are organized into oligomeric, probably trimeric spikes displayed on the surface of the virion. These envelope complexes are anchored in the viral membrane by the gp41 transmembrane envelope glycoprotein. The surface of the spike is composed primarily of the exterior envelope glycoprotein, gp120, associated by non-covalent interactions with each subunit of the trimeric gp41 glycoprotein complex 3,4 . Comparison of the gp120 sequences of different primate immunodeficiency viruses identified five variable regions (V1-V5) (ref. 5 ). The first four variable regions form surface-exposed loops that contain disulphide bonds at their bases 6 . The conserved gp120 regions form discontinuous structures important for the interaction with the gp41 ectodomain and with the viral receptors on the target cell. Both conserved and variable gp120 regions are extensively glycosylated 6 . The variability and glycosylation of the gp120 surface probably modulate the immunogenicity and antigenicity of the gp120 glycoprotein, which is the main target for neutralizing antibodies elicited during natural infection 7 .Entry of primate immunodeficiency viruses into the host cell involves the binding of the gp120 envelope glycoprotein to the CD4 glycoprotein, which serves as the primary receptor. The gp120 glycoprotein binds to the most amino-terminal of the four immunoglobulin-like domains of CD4. S...

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Atomic structure of a fragment of human CD4 containing two immunoglobulin-like domains

Cited by 544 publications

References 62 publications

The CD200 and CD200 receptor cell surface proteins interact through their N‐terminal immunoglobulin‐like domains

The CD200 and CD200 receptor cell surface proteins interact through their N‐terminal immunoglobulin‐like domains

Mutations in CD8 that affect interactions with HLA class I and monoclonal anti-CD8 antibodies.

Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody

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