The Antigenic Structure of Proteins: A Reappraisal

Benjamin, David C.; Berzofsky, Jay A.; East, I.J.; Gurd, Frank R. N.; Hannum, Charles; Leach, Sydney; Margoliash, E.; Michael, J. Gabriel; Miller, Alexander; Prager, Ellen M.; Reichlin, Morris; Sercarz, Eli E.; Smith‐Gill, Sandra J.; Todd, P.E.E.; Wilson, Allan C.

doi:10.1146/annurev.iy.02.040184.000435

Cited by 920 publications

(300 citation statements)

References 59 publications

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“…This is in agreement with the knowledge that T cells do not discriminate between native and denatured antigens [33], since both forms are taken up by APC, processed and presented to specific T cell lines in association with MHC class II molecules [34]. This implies that similar peptides result from the processing of denatured and native antigen since in general antigen-specific T cell clones fail to discriminate between these forms [35], with a few exceptions [36].…”

Section: Discusstonsupporting

confidence: 87%

Inhibitory activity of HIV envelope gp120 dominates over its antigenicity for human T cells

Manca

Walker

Newell

et al. 1992

Clinical and Experimental Immunology

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SUMMARYHIV-1 envelope glycoprotein (gpl20), as a CD4-binding reactant, has been shown to inhibit in its native form human T cell responses to several antigens. Here we show that gp 120 in soluble form also inhibits activation ofa specific human T cell line that responds to gpl20-pulsed autologous antigenpresenting cells. In addition the inhibitory property of gpl20 for antigen-driven Tcell proliferation depends upon its ability to bind CD4 and is lost when CD4-binding capacity is abolished by denaturation, or blocked by complexing with soluble CD4 or with polyclonal antibodies. In contrast, antigenicity of denatured or complexed gpl 20 for specific human T cells is preserved. Similar effects are also observed with another CD4-binding reactant (i,e, anti-Leu 3a MoAb), which stimulates and/ or inhibits human T cells specific for mouse immunoglobulins depending on native or denatured conformation.Keywords gpl20 antigenicity T clones gpl20-CD4 complexes CD4 binding proteins tNTRODUCTtONThe antigen-specific response ofthe CD4+ T lymphocyte subset is MHC class II restricted [1], Interaction between CD4 and MHC Class II facilitates functional association between T lymphocytes and the antigen-presenting cells (APC) and enhances T cell receptor interaction with the presented peptide antigen [2,3], The envelope glycoprotein of HIV-1, gpl60, is composed of two moieties, gpl20 and gp41, one of which (gpl20) binds CD4 with high affinity [4], Interaction between gpl20 and CD4 accounts for the cellular tropism of the HIV-1 retrovirus [5,6], Antigen-specific activation ofT cells restricted to MHC class II can be prevented by the interaction of gpl20 with CD4, as well as by MoAb which block both MHC class II-CD4 association and gpl20-CD4 binding [7][8][9][10][11][12][13][14][15],The immunogenic properties of gpl20 have been demonstrated in both infected and uninfected individuals [16][17][18][19][20][21][22][23], Human T cell lines specific for gpl20 can also be generated in vitro from seronegative donors by pulsing irradiated autologous APC with gpl20, or exposing lymphocytes to low doses of soluble gpl20 [24][25][26], Since antigen processing by APC involves antigen fragmentation and loss of native conformation [27], it is likely that degradation of gpl20 results in loss of CD4-binding capacity and henceinhibitory activity of gpl 20 which is strictly dependent on native conformation. To test this hypotheCorrespondence: F, Manca MD, Department of Immunology, University of Genoa, San Martino Hospital, viale Benedetto XV, 10, 16132 Genoa, Italy, sis we compared the CD4-binding capacity of gpl20 with (i) inhibitory activity (i,e, capacity to interfere with antigen-driven T cell activation) and (ii) antigenicity (i,e, ability to stimulate gpl20-specific human T cell lines and clones).In a comparable system we also demonstrate that another CD4 binding reactant (the CD4-specific MoAb anti-Leu 3a) which inhibits antigen-specific T cell responses in native form, retains its antigenicity for human T cells specific for mouse immunoglobul...

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Section: Discusstonsupporting

confidence: 87%

Inhibitory activity of HIV envelope gp120 dominates over its antigenicity for human T cells

Manca

Walker

Newell

et al. 1992

Clinical and Experimental Immunology

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“…Another concern about the existence of isofunctional residues arises for workers who try to find the residues comprising the epitope -the combining region of the antigen involved in antigen-antibody association -by comparing the association of a series of homologous protein antigens (especially if the three-dimensional structure of one member is known) and inferring the epitope from the observed changes in binding (for reviews see Benjamin et al [1984] and Davies et al [1988]). This method has been greatly extended to protein-protein association by the widely used alanine scan of Cunningham and Wells (1989) where a large set of mutants of one of the partner proteins is prepared, with systematic one-at-a-time replacements of existing residues by Ala.…”

Section: Is0 Functional Residuesmentioning

confidence: 99%

Binding of amino acid side chains to preformed cavities: Interaction of serine proteinases with turkey ovomucoid third domains with coded and noncoded P₁ residues

Bigler

Park

et al. 1993

Protein Science

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In the association of serine proteinases with their cognate substrates and inhibitors an important interaction is the fitting of the PI side chain of the substrate or inhibitor into a preformed cavity of the enzyme called the SI pocket. In turkey ovomucoid third domain, which is a canonical protein proteinase inhibitor, the PI residue is Leu18. Here we report the values of equilibrium constants, K,, for turkey ovomucoid third domain and 13 additional Leul8X variants with six serine proteinases: bovine 01 chymotrypsin A, porcine pancreatic elastase, subtilisin Carlsberg, Streptomyces griseus proteinases A and B, and human leukocyte elastase. Eight of the Xs are coded amino acids: Ala, Ser, Val, Met, Gln, Glu, Lys, and Phe, and five are noncoded: Abu, Ape, Ahx, Ahp, and Hse. They were chosen to simplify the interamino acid comparisons. In the homologous series of straight-chain side chains Ala, Abu, Ape, Ahx, Ahp, free energy of binding decreases monotonically with the side-chain length for chymotrypsin with large binding pocket, but even for this enzyme shows curvature. For the two S. griseus enzymes a minimum appears to be reached at Ahp. A minimum is clearly evident for the two elastases, where increasing the side-chain length from Ahx to Ahp greatly weakens binding, but much more so for the apparently more rigid pancreatic enzyme than for the more flexible leukocyte enzyme. 0-Branching (Ape/Val) is very deleterious for five of the six enzymes; it is only slightly deleterious for the more flexible human leukocyte elastase. The effect of y-branching (Ahx/Leu), of introduction of heteroatoms (Abu/Ser), (Ape/Hse), and (Ahx/Met), and of introduction of charge (Gln/Glu) and (Ahp/Lys) are tabulated and discussed. An important component of the free energy of interaction is the distortion of the binding pocket by bulky or branched side chains.Most of the variants studied were obtained by enzymatic semisynthesis. X" variants of the 6-18 peptide GlyNH, were synthesized and combined with natural reduced peptide 19-56. Disulfide bridges were formed. The GlyNH, was removed and the reactive-site peptide bond Xls-Glu19 was synthesized by complex formation with proteinase K. The resultant complexes were dissociated by sudden pH drop. This kinetically controlled dissociation afforded virgin, reactive-site-intact inhibitor variants.Keywords: binding of amino acid side chains; deformability of binding pockets; enzymatic semisynthesis; noncoded amino acid residues; ovomucoid third domains; serine proteinases Abbreviations: P I , the residue contributing the carbonyl portion to the reactive-site peptide bond; SI, the pocket in the enzyme to which the P I residue binds; OMXXX3, ovomucoid third domain, with XXX designating the species; TKY, turkey; SVP, silver pheasant; SWN, black swan; WTD, West Indian tree duck; MNQ, Montezuma quail; X"OMTKY3, X residue replaces Leu" in OMTKY3 (Fig. 1); Abu CY, aminobutyric acid; Ape CY, aminopentanoic acid (norvaline); Ahx CY, aminohexanoic acid (norleucine); Ahp a , aminoheptanoic acid; H...

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“…Conversely, the other view argues that protein surfaces contain a very limited number of exclusive sites that are inherently antigenic. The fact that interior parts of the protein, which are naturally not exposed and as such not expected to possess antigenic characteristics, are quite capable of stimulating production of specific antibodies (Benjamin et al, 1984) has been proposed as evidence in support of the first view. Yet, in support of the second view is the fact that during the course of the natural response to a given antigen very few locations on the surface of a protein are required for the generation of the overwhelming majority of antibodies produced against it (Hopp, 1986).…”

Section: Introductionmentioning

confidence: 99%

Computational characterization of B-cell epitopes

Rubinstein

Mayrose

Halperin

et al. 2008

Molecular Immunology

217

233

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Characterizing B-cell epitopes is a fundamental step for understanding the immunological basis of bio-recognition. To date, epitope analyses have either been based on limited structural data, or sequence data alone. In this study, our null hypothesis was that the surface of the antigen is homogeneously antigenic. To test this hypothesis, a large dataset of antibody-antigen complex structures, together with crystal structures of the native antigens, has been compiled. Computational methods were developed and applied to detect and extract physico-chemical, structural, and geometrical properties that may distinguish an epitope from the remaining antigen surface. Rigorous statistical inference was able to clearly reject the null hypothesis showing that epitopes are distinguished from the remaining antigen surface in properties such as amino acid preference, secondary structure composition, geometrical shape, and evolutionary conservation. Specifically, epitopes were found to be significantly enriched with tyrosine and tryptophan, and to show a general preference for charged and polar amino acids. Additionally, epitopes were found to show clear preference for residing on planar parts of the antigen that protrude from the surface, yet with a rugged surface shape at the atom level. The effects of complex formation on the structural properties of the antigen were also computationally characterized and it is shown that epitopes undergo compression upon antibody binding. This correlates with the finding that epitopes are enriched with unorganized secondary structure elements that render them flexible. Thus, this study extends the understanding of the underlying processes required for antibody binding, and reveals new aspects of the antibody-antigen interaction.

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The Antigenic Structure of Proteins: A Reappraisal

Cited by 920 publications

References 59 publications

Inhibitory activity of HIV envelope gp120 dominates over its antigenicity for human T cells

Inhibitory activity of HIV envelope gp120 dominates over its antigenicity for human T cells

Binding of amino acid side chains to preformed cavities: Interaction of serine proteinases with turkey ovomucoid third domains with coded and noncoded P₁ residues

Computational characterization of B-cell epitopes

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The Antigenic Structure of Proteins: A Reappraisal

Cited by 920 publications

References 59 publications

Inhibitory activity of HIV envelope gp120 dominates over its antigenicity for human T cells

Inhibitory activity of HIV envelope gp120 dominates over its antigenicity for human T cells

Binding of amino acid side chains to preformed cavities: Interaction of serine proteinases with turkey ovomucoid third domains with coded and noncoded P1 residues

Computational characterization of B-cell epitopes

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Product

Resources

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Binding of amino acid side chains to preformed cavities: Interaction of serine proteinases with turkey ovomucoid third domains with coded and noncoded P₁ residues