The Zinc-Dependent Major Histocompatibility Complex Class II Binding Site of Streptococcal Pyrogenic Exotoxin C Is Critical for Maximal Superantigen Function and Toxic Activity

Tripp, Timothy J.; McCormick, John K.; Webb, Jennifer M.; Schlievert, Patrick M.

doi:10.1128/iai.71.3.1548-1550.2003

Cited by 20 publications

(19 citation statements)

References 14 publications

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“…2C). These data suggest that there are two independent interfaces on SpeC responsible for the LG-2 cell aggregation phenotype, one that is represented by the zinc-dependent, high-affinity MHC II interface (6,29), and a second within the ␤-barrel domain that is consistent with characterized low-affinity MHC II interfaces (2)(3)(4)8).…”

Section: Lg-2 Cell Aggregation By the Spec Mutants Is Indicative Of Msupporting

confidence: 50%

“…From the crystal structure of SpeC, the dimer interface occupied the generic, lowaffinity MHC II domain and thus precluded the low-affinity interaction (47). However, other work using limited mutational analysis has shown that SpeC likely possesses an alternative MHC II binding interface (29,48) analogous to the structurally characterized low-affinity interfaces of SEA, SEB and SEC 3 (2,4,8). Thus, to resolve the issue regarding the presence or absence of a potential low-affinity MHC II binding interface and to understand the molecular basis by which SpeC binds MHC II through this putative interface, we performed alanine-scanning mutagenesis of all SpeC residues within the ␤-barrel domain that could potentially contact MHC II.…”

Section: Generation Of the Spec Mutantsmentioning

confidence: 99%

“…Cells not treated with SAg were used as background control. Additional controls included cells treated with the SpeC Y15A mutant known to be critical for engagement of TCR (13,49) and the SpeC D203A mutant known to be critical for engagement of MHC␤ through the high-affinity interface (6,29). Data shown are the average Ϯ SEM for at least 10 independent experiments.…”

Section: Mutations Within the Putative Low-affinity Mhc II Binding Inmentioning

confidence: 99%

“…These mutations were initially based on the four structurally characterized SAg/low-affinity MHC II interactions including TSST-1/HLA-DR1 (3), SEB/HLA-DR1 (2), SEA D227A /HLA-DR1 (8), and SEC 3 /HLA-DR1 (4). A total of 20 mutations were engineered that cover 2,192 Å (2) of the SpeC surface, as well as two additional control mutations located within the characterized zinc-mediated, high-affinity MHC␤ (SpeC D203A ) and TCR (SpeC Y15A ) interfaces (6, 13), each of which are known to disrupt these respective interactions (29,49).…”

Section: Generation Of the Spec Mutantsmentioning

confidence: 99%

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Molecular Requirements for MHC Class II α-Chain Engagement and Allelic Discrimination by the Bacterial Superantigen Streptococcal Pyrogenic Exotoxin C

Kasper

Wang

Rahman

et al. 2008

The Journal of Immunology

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Superantigens (SAgs) are microbial toxins that bind to both TCR β-chain variable domains (Vβs) and MHC class II molecules, resulting in the activation of T cells in a Vβ-specific manner. It is now well established that different isoforms of MHC II molecules can play a significant role in the immune response to bacterial SAgs. In this work, using directed mutational studies in conjunction with functional analyses, we provide a complete functional map of the low-affinity MHC II α-chain binding interface of the SAg streptococcal pyrogenic exotoxin C (SpeC) and identify a functional epitope in the β-barrel domain that is required for the activation of T cells. Using cell lines that exclusively express individual MHC II isoforms, our studies provide a molecular basis for the selectivity of SpeC-MHC II recognition, and provide one mechanism by how SAgs are capable of distinguishing between different MHC II alleles.

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Section: Lg-2 Cell Aggregation By the Spec Mutants Is Indicative Of Msupporting

confidence: 50%

Section: Generation Of the Spec Mutantsmentioning

confidence: 99%

Section: Mutations Within the Putative Low-affinity Mhc II Binding Inmentioning

confidence: 99%

Section: Generation Of the Spec Mutantsmentioning

confidence: 99%

See 2 more Smart Citations

Molecular Requirements for MHC Class II α-Chain Engagement and Allelic Discrimination by the Bacterial Superantigen Streptococcal Pyrogenic Exotoxin C

Kasper

Wang

Rahman

et al. 2008

The Journal of Immunology

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“…Functional Epitope Mapping on the Surface of the hV␤2.1 TCR for TSST-1 and SpeC-From prior co-crystallization studies (12,16,20,21), and using the wild-type hV␤2-TSST complex solved here, coupled with corroborating mutagenesis data (11,26,(33)(34)(35), supramolecular T cell activation complexes can be modeled for both TSST-1 and SpeC (Fig. 2).…”

Section: Resultsmentioning

confidence: 77%

The T Cell Receptor β-Chain Second Complementarity Determining Region Loop (CDR2β) Governs T Cell Activation and Vβ Specificity by Bacterial Superantigens

Rahman

Bonsor

Herfst

et al. 2011

Journal of Biological Chemistry

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Superantigens (SAgs) are microbial toxins defined by their ability to activate T lymphocytes in a T cell receptor (TCR)␤-chain variable domain (V␤)-specific manner. Although existing structural information indicates that diverse bacterial SAgs all uniformly engage the V␤ second complementarity determining region (CDR2␤) loop, the molecular rules that dictate SAg-mediated T cell activation and V␤ specificity are not fully understood. Herein we report the crystal structure of human V␤2.1 (hV␤2.1) in complex with the toxic shock syndrome toxin-1 (TSST-1) SAg, and mutagenesis of hV␤2.1 indicates that the non-canonical length of CDR2␤ is a critical determinant for recognition by TSST-1 as well as the distantly related SAg streptococcal pyrogenic exotoxin C. Frame work (FR) region 3 is uniquely critical for TSST-1 function explaining the fine V␤-specificity exhibited by this SAg. Furthermore, domain swapping experiments with SAgs, which use distinct domains to engage both CDR2␤ and FR3/4␤ revealed that the CDR2␤ contacts dictate T lymphocyte V␤-specificity. These findings demonstrate that the TCR CDR2␤ loop is the critical determinant for functional recognition and V␤-specificity by diverse bacterial SAgs.Antigen-specific T cell-mediated immunity is initiated through the interaction of the ␣␤ T cell receptor (TCR) 3 with a processed peptide antigen presented within the distal groove of self major histocompatibility (pMHC) complexes. A general consensus for typical TCR-pMHC recognition is that germ line encoded complementarity determining region loops (CDR) 1 and CDR2 of both the TCR ␣-and ␤-chains primarily recognize the ␣-helices of self pMHC complexes, while peptide specificity is mainly driven by the CDR3 loops (1, 2). Bacterial superantigens (SAgs) are potent immunostimulatory toxins that distort the molecular 'rules' which dictate normal TCR-pMHC class II (pMHC II) interactions. SAgs function by binding to lateral surfaces on both TCR ␤-chain variable domains (V␤) (3) and pMHC II complexes (4), resulting in the activation of T cells in a V␤-restricted manner (5). In the standard TCR-SAg-pMHC II model, the TCR ␤-chain, and pMHC II ␣-chain are wedged apart by the SAg such that the CDR3 loops of the ␣␤ TCR cannot interact directly with the antigenic peptide contained within the pMHC II complexes (6). Because SAgs bind the germ line encoded V␤ region, while essentially ignoring the highly diverse CDR3␤ loop, the frequency of T cells responding to SAg exposure exceeds that of conventional peptide antigens by many orders of magnitude. Through this mechanism, SAgs may ultimately mediate a cytokine storm disease known as the toxic shock syndrome (7).The bacterial pathogens Staphylococcus aureus and Streptococcus pyogenes are each capable of producing multiple distinct bacterial SAgs that fall into at least five distinct evolutionary groups, designated as I through V (Fig. 1A) (7, 8), that share a conserved three-dimensional fold (9) (Fig. 1B). Despite this conserved structure, SAgs can bind to pMHC II through diverse m...

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Streptococcal Superantigens

Babbar¹

2015

SpringerBriefs in Microbiology

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The Zinc-Dependent Major Histocompatibility Complex Class II Binding Site of Streptococcal Pyrogenic Exotoxin C Is Critical for Maximal Superantigen Function and Toxic Activity

Cited by 20 publications

References 14 publications

Molecular Requirements for MHC Class II α-Chain Engagement and Allelic Discrimination by the Bacterial Superantigen Streptococcal Pyrogenic Exotoxin C

Molecular Requirements for MHC Class II α-Chain Engagement and Allelic Discrimination by the Bacterial Superantigen Streptococcal Pyrogenic Exotoxin C

The T Cell Receptor β-Chain Second Complementarity Determining Region Loop (CDR2β) Governs T Cell Activation and Vβ Specificity by Bacterial Superantigens

Streptococcal Superantigens

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