Human immunodeficiency virus gp120 binding C'C" ridge of CD4 domain 1 is also involved in interaction with class II major histocompatibility complex molecules.

Moebius, Ulrich; Clayton, Linda K.; Abraham, Sheena; Diener, Andrew C.; Londoño, Juan José Yunis; Harrison, Stephen C.; Reinherz, Ellis L.

doi:10.1073/pnas.89.24.12008

Cited by 73 publications

(66 citation statements)

References 46 publications

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“…COS-7 cells transfected with pcDNA3 vector alone served as negative controls, which showed no rosette formation. Other studies have demonstrated that the enumeration of rosetting as performed here correlates well with quantitative cell binding assays employing radiolabeled Raji cells (16).…”

Section: Methodssupporting

confidence: 63%

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Bioactive Peptide Design Based on Protein Surface Epitopes

Satoh

Aramini

Song

et al. 1997

Journal of Biological Chemistry

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The interaction between CD4 and major histocompatibility complex class II proteins provides a critical coreceptor function for the activation of CD4 ؉ T cells implicated in the pathogenesis of a number of autoimmune diseases and transplantation responses. A small synthetic cyclic heptapeptide was designed and shown by high resolution NMR spectroscopy to closely mimic the CD4 domain 1 CC surface loop. This peptide effectively blocked stable CD4-major histocompatibility complex class II interaction, possessed significant immunosuppressive activity in vitro and in vivo, and strongly resisted proteolytic degradation. These results demonstrate the therapeutic potential of this peptide as a novel immunosuppressive agent and suggest a general strategy of drug design by using small conformationally constrained peptide mimics of protein surface epitopes to inhibit protein interactions and biological functions.Protein-protein interactions play an important role in a wide range of physiological and pathological processes. The interactions between proteins generally involve large interfaces with many intermolecular contacts (1). As such, the rational design of small molecular inhibitors of these surfaces has long been considered a formidable challenge. Despite this commonly held view, recent studies indicate that proteins may actually interact through small surface binding epitopes, as in the human growth hormone-receptor complex (2) and the erythropoietinreceptor complex (3). These findings raise an intriguing possibility that mimics of such small binding epitopes may be sufficient for blockade of a large protein-protein interface. However, the general applicability of this hypothesis and its implications for rational drug design remain to be tested and demonstrated in different biological systems. Undoubtedly, the development of a general approach to inhibit protein-protein interactions will have a tremendous impact on understanding the structural basis of these interactions and in developing new therapeutic strategies for many human diseases.CD4 is a glycoprotein consisting of four Ig-like extracellular domains (D1-D4) 1 and is expressed on the surface of helper T cells (4). Major histocompatibility complex (MHC) class II is a heterodimeric glycoprotein expressed on the surface of antigenpresenting cells and binds antigenic peptides for recognition by the T cell receptor. The interaction between CD4 and nonpolymorphic regions of the MHC class II molecule is critical for optimal CD4 ϩ T cell activation, with CD4 serving as a coreceptor for T cell receptor-antigen engagement (5). Numerous mutation studies have been performed to determine the regions of CD4 involved in MHC class II binding, and like many protein-protein complexes, the interface is generally believed to involve a large surface area of both D1 and D2, with many contact sites (6 -9). CD4 ϩ T cells participate in the pathogenesis of a number of immune-based human conditions, including autoimmune diseases, allogenic organ transplant rejection, and graft versus h...

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Section: Methodssupporting

confidence: 63%

“…CD4-MHC class II binding studies, using a cell rosetting assay (5,16), were performed to test this hypothesis. Peptide IV inhibited rosette formation by as much as 50% in a concentrationdependent manner (Fig.…”

Section: Fig 4 Inhibitory Effect Of the Cyclic Heptapeptide IV (Cnsmentioning

confidence: 99%

Bioactive Peptide Design Based on Protein Surface Epitopes

Satoh

Aramini

Song

et al. 1997

Journal of Biological Chemistry

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“…Other studies have shown that the enumeration of rosetting as performed here correlates well with quantitative cell binding assays employing radiolabeled Raji cells (20).…”

Section: Animals Female Sjl͞j H2mentioning

confidence: 56%

“…The inhibition of stable CD4-MHC class II binding by the compounds selected from computer screening studies was assessed in a standard cell adhesion assay that has been shown by several laboratories to accurately reflect this functional interaction (8,16,20). Following a modified procedure of Moebius et al (20), 5 ϫ 10 4 COS-7 cells per well of a 6-well plate were transfected with T4-pcDNA3 (Invitrogen) by DOSPER liposomal transfection (Boehringer Mannheim) according to the supplier's protocol for the reagent.…”

Section: Animals Female Sjl͞j H2mentioning

confidence: 99%

A computer screening approach to immunoglobulin superfamily structures and interactions: Discovery of small non-peptidic CD4 inhibitors as novel immunotherapeutics

Song

Gao

Satoh

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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The interaction between CD4 and major histocompatibility complex (MHC) class II proteins is critical for the activation of CD4 ؉ T cells, which are involved in transplantation reactions and a number of autoimmune diseases. In this study we have identified a CD4 surface pocket as a functional epitope implicated in CD4-MHC class II interaction and T-cell activation. A computer-based strategy has been used to screen Ϸ150,000 non-peptidic organic compounds in a molecular data base and to identify a group of compounds as ligands of the proposed CD4 surface pocket. These small organic compounds have been shown to specifically block stable CD4-MHC class II binding, and exhibit significant inhibition of immune responses in animal models of autoimmune disease and allograft transplant rejection, suggesting their potential as novel immunosuppressants. This structurebased computer screening approach may have general implications for studying many immunoglobulin-like structures and interactions that share similar structural features. Furthermore, the results from this study have demonstrated that the rational design of small non-peptidic inhibitors of large protein-protein interfaces may indeed be an achievable goal.Protein-protein interactions are critical events in many biological processes. In general, these interactions involve large interfaces with many intermolecular contacts (1, 2). As such, it has long been a great challenge to design small molecular inhibitors of these surfaces in either peptide or more preferably non-peptide form. Recently, it has been suggested that proteins may actually interact through small critical surfacebinding epitopes, as in the cases of the human growth hormone-(3) and the erythropoietin-receptor complexes (4). These findings raise the intriguing possibility that inhibitors of these small binding epitopes may be sufficient for the effective blockade of large protein-protein interfaces. However, the general validity of this hypothesis and its implication for rational drug design remain to be tested and demonstrated in different biological systems. Undoubtedly, the development of a general approach to inhibit protein-protein interactions will have a tremendous impact on the understanding of the structural basis of these interactions and the design of new therapeutic strategies for many human diseases.An important category of protein-protein interactions are those among the immunoglobulin (Ig) superfamily of molecules, which includes a large group of cell surface structures that are characterized by a conserved Ig-like folding (5). The members of the Ig superfamily mediate diverse biological functions in immunity, particularly in cell surface recognition, and thus are attractive targets for drug design studies. In an attempt to better understand the structural basis of Ig superfamily interactions, we have focused on the interaction between the CD4 protein and the major histocompatibility complex (MHC) class II protein. CD4 is a glycoprotein expressed on the surface of helper T cells,...

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“…Interaction with pMHCI is via the six antibody-like CDR loops, three from each subunit Ig domain (47,48). In contrast, CD4 interaction with pMHCII involves the D1-D2 module including residues outside of the CDR regions (13,49,50). Perhaps more importantly, the membrane proximal CD4 segment is not a flexible stalk but rather is composed of two Ig-like domains.…”

Section: Discussionmentioning

confidence: 99%

T Cell Receptor Binding to a pMHCII Ligand Is Kinetically Distinct from and Independent of CD4

Xiong

Kern

Chang

et al. 2001

Journal of Biological Chemistry

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Immune recognition of pMHCII ligands by a helper T lymphocyte involves its antigen-specific T cell receptor (TCR) and CD4 coreceptor. We have characterized the binding of both molecules to the same pMHCII. The D10 ␣␤ TCR heterodimer binds to conalbumin/I-A k with virtually identical kinetics and affinity as the single chain V␣V␤ domain module (scD10) (K d ‫؍‬ 6 -8 M). The CD4 ectodomain does not alter either interaction. Moreover, CD4 alone demonstrates weak pMHCII binding (K d ‫؍‬ 200 M), with no discernable affinity for the ␣␤ TCR heterodimer. Hence, rather than providing a major contribution to binding energy, the critical role for the coreceptor in antigen-specific activation likely results from transient inducible recruitment of the CD4 cytoplasmic tail-associated lck tyrosine kinase to the pMHCII-ligated TCR complex.The transmembrane CD4 glycoprotein expressed on the surface of a majority of thymocytes as well as helper T lymphocytes is centrally involved in MHC 1 class II-restricted differentiation and activation (1-6). The extracellular rod-like segment of CD4 consists of four concatamerized Ig-like domains (D1-D4), a single transmembrane-spanning segment, and a short cytoplasmic tail (7-10). The membrane distal D1 and D2 domains bind to the nonpolymorphic ␤2 domain of MHC class II molecules, whereas the membrane proximal D3-D4 module is thought to be involved in both CD4 oligomerization and TCR interaction (11)(12)(13)(14)(15)(16)(17). During antigen recognition of peptides bound to MHC class II molecules (pMHCII), CD4 and TCR colocalize, interacting with the same pMHCII molecule (18 -20). Hence, CD4 has been termed a coreceptor (21). The cytoplasmic tail of CD4 is noncovalently associated with p56 lck , a Src-like tyrosine kinase, and also contains membrane proximal palmitoylation sites that direct CD4 to lipid rafts enriched in additional signaling molecules (22-25). p56 lck initiates CD4-and TCR-based signal transduction and facilitates the physical coassociation of the TCR and CD4 coreceptor (26).To date, biophysical parameters of CD4 interaction with pMHCII and TCR ectodomain components have not been measured. Attempts to quantitate TCR-independent binding between CD4 and pMHCII in human and mouse systems using cell-based assays and soluble CD4 ectodomain constructs have suggested a weak interaction (K d Ͼ 100 M) (15, 27, 28). However, the precise affinity and kinetics of binding are unknown. Furthermore, whether CD4 ectodomain interaction with pMH-CII is modulated by the TCR or, alternatively, whether prior CD4-pMHCII interaction alters the MHC antigen-presenting platform, augmenting subsequent TCR affinity for its ligand is uncertain. In the present study, we have utilized highly purified recombinant TCR, pMHCII, and CD4 ectodomains to address these questions. The results offer insight into the fundamental nature of CD4-pMHCII interaction, further elucidate the role of CD4 in class II MHC-restricted TCR recognition, and indicate that if an interaction exists between CD4 and TCR extracellular segm...

show abstract

Human immunodeficiency virus gp120 binding C'C" ridge of CD4 domain 1 is also involved in interaction with class II major histocompatibility complex molecules.

Cited by 73 publications

References 46 publications

Bioactive Peptide Design Based on Protein Surface Epitopes

Bioactive Peptide Design Based on Protein Surface Epitopes

A computer screening approach to immunoglobulin superfamily structures and interactions: Discovery of small non-peptidic CD4 inhibitors as novel immunotherapeutics

T Cell Receptor Binding to a pMHCII Ligand Is Kinetically Distinct from and Independent of CD4

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