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Structure of Staphylococcal Enterotoxin E in Complex with TCR Defines the Role of TCR Loop Positioning in Superantigen Recognition.

Rödström KE, Regenthal P, Lindkvist-Petersson K - PLoS ONE (2015)

Bottom Line: Here, we present the structure of staphylococcal enterotoxin E (SEE) in complex with a human T cell receptor, as well as the unligated T cell receptor structure.In particular, the HV4 loop moves to circumvent steric clashes upon complex formation.In addition, a predicted ternary model of SEE in complex with both TCR and MHC class II displays intermolecular contacts between the TCR α-chain and the MHC, suggesting that the TCR α-chain is of importance for complex formation.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medical Science, Lund University, BMC C13, 22 184, Lund, Sweden.

ABSTRACT
T cells are crucial players in cell-mediated immunity. The specificity of their receptor, the T cell receptor (TCR), is central for the immune system to distinguish foreign from host antigens. Superantigens are bacterial toxins capable of inducing a toxic immune response by cross-linking the TCR and the major histocompatibility complex (MHC) class II and circumventing the antigen specificity. Here, we present the structure of staphylococcal enterotoxin E (SEE) in complex with a human T cell receptor, as well as the unligated T cell receptor structure. There are clear structural changes in the TCR loops upon superantigen binding. In particular, the HV4 loop moves to circumvent steric clashes upon complex formation. In addition, a predicted ternary model of SEE in complex with both TCR and MHC class II displays intermolecular contacts between the TCR α-chain and the MHC, suggesting that the TCR α-chain is of importance for complex formation.

No MeSH data available.


Related in: MedlinePlus

Comparison between structurally determined CDR2 loops.(A) Close-up view of the CDR2β loop of 23 structurally determined TCRs. TRBV domains with coloured loops have been reported to bind SEE, while the non-binders are shown in grey; TRBV4-1 (pink), TRBV5-1 (orange), TRBV7-2 (green), TRBV7-3 (purple), TRBV7-8 (cyan), TRBV7-9 (blue), TRBV11-2 (brown), TRBV12-4 (red), and TRBV14 (yellow), (B) comparison between the SEE-TRBV7-9 structure in beige and blue, respectively, and TRBV19 in grey, which do not bind SEE. The hydrogen bond pattern to the backbone of CDR2 and the C” strand is shown with dotted lines.
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pone.0131988.g003: Comparison between structurally determined CDR2 loops.(A) Close-up view of the CDR2β loop of 23 structurally determined TCRs. TRBV domains with coloured loops have been reported to bind SEE, while the non-binders are shown in grey; TRBV4-1 (pink), TRBV5-1 (orange), TRBV7-2 (green), TRBV7-3 (purple), TRBV7-8 (cyan), TRBV7-9 (blue), TRBV11-2 (brown), TRBV12-4 (red), and TRBV14 (yellow), (B) comparison between the SEE-TRBV7-9 structure in beige and blue, respectively, and TRBV19 in grey, which do not bind SEE. The hydrogen bond pattern to the backbone of CDR2 and the C” strand is shown with dotted lines.

Mentions: Staphylococcal enterotoxin E has a rather broad TRBV profile, and activates T cells bearing TRBV4, 5-1, 7, 11, 12, 14, 15, and 18 [11]. Commonly, the CDR2 loop and C” strand can adopt two different conformations in TRBV domains. The CDR2 loops and C” strands from 23 different structurally determined TRBVs [28, 29, 55–73], with either of these two conformations, were aligned (Fig 3A). Notably, eleven of these TRBV domains share the same C” strand conformation as TRBV7-9, whereas the TRBV domains that are not activated by SEE adopt the other conformation (Fig 3A). Clearly, the hydrogen bond pattern formed by SEE to TRBV7-9 cannot be formed to TRBV domains exhibiting the other conformation, as exemplified by TRBV19 (Fig 3B). Eight out of the eleven with the same CDR2 loop and C” strand conformation, are activated by SEE. Due to the rather broad reactivity of SEE and the common CDR2 structure of TRBVs recognized by SEE, it is likely that this SAg discriminates between TRBV domains partly based on CDR2 loop conformation (Fig 3A) [11]. However, three TRBV domains with the same CDR2 conformation are still not recognized by SEE: TRBV9, TRBV5-6 and TRBV5-8 (Fig 3A) [11]. Another important player for the TRBV specificity for SEE is the HV4 loop. It has been shown that T cells expressing the TRBV7-2*01 allele, with a Gly84b (IMGT numbering) in the HV4 loop [63], which corresponds to Gly73b in TRBV7-9, are activated by SEE, while TRBV7-2*02 with a glutamate instead of a glycine, is not activated by SEE [5]. Hence, it is likely that a large, charged amino acid in this position negatively affects the binding of SEE to TRBV. TRBV9 has an aspartate in this position [66], and thus this amino acid likely contributes to the ruling out of SEE recognition. Furthermore, TRBV9, TRBV5-6, and TRBV5-8 all have a glutamate at position 64 (IMGT numbering), in the CDR2 loop [57, 58, 66], whereas the corresponding residue in TRBV7-9 is Ala54b. This side-chain points towards residues Tyr205s and Pro206s in SEE. Thus, substituting the alanine to a glutamate would result in a negatively charged residue in a hydrophobic environment. In addition, the neighboring residue Asp207s may provide a negative charge, resulting in repulsion of a glutamate. Also, this region including both Pro206s and Asp207s, have been confirmed to be crucial for determining the TRBV specificity of SEE [74].


Structure of Staphylococcal Enterotoxin E in Complex with TCR Defines the Role of TCR Loop Positioning in Superantigen Recognition.

Rödström KE, Regenthal P, Lindkvist-Petersson K - PLoS ONE (2015)

Comparison between structurally determined CDR2 loops.(A) Close-up view of the CDR2β loop of 23 structurally determined TCRs. TRBV domains with coloured loops have been reported to bind SEE, while the non-binders are shown in grey; TRBV4-1 (pink), TRBV5-1 (orange), TRBV7-2 (green), TRBV7-3 (purple), TRBV7-8 (cyan), TRBV7-9 (blue), TRBV11-2 (brown), TRBV12-4 (red), and TRBV14 (yellow), (B) comparison between the SEE-TRBV7-9 structure in beige and blue, respectively, and TRBV19 in grey, which do not bind SEE. The hydrogen bond pattern to the backbone of CDR2 and the C” strand is shown with dotted lines.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4492778&req=5

pone.0131988.g003: Comparison between structurally determined CDR2 loops.(A) Close-up view of the CDR2β loop of 23 structurally determined TCRs. TRBV domains with coloured loops have been reported to bind SEE, while the non-binders are shown in grey; TRBV4-1 (pink), TRBV5-1 (orange), TRBV7-2 (green), TRBV7-3 (purple), TRBV7-8 (cyan), TRBV7-9 (blue), TRBV11-2 (brown), TRBV12-4 (red), and TRBV14 (yellow), (B) comparison between the SEE-TRBV7-9 structure in beige and blue, respectively, and TRBV19 in grey, which do not bind SEE. The hydrogen bond pattern to the backbone of CDR2 and the C” strand is shown with dotted lines.
Mentions: Staphylococcal enterotoxin E has a rather broad TRBV profile, and activates T cells bearing TRBV4, 5-1, 7, 11, 12, 14, 15, and 18 [11]. Commonly, the CDR2 loop and C” strand can adopt two different conformations in TRBV domains. The CDR2 loops and C” strands from 23 different structurally determined TRBVs [28, 29, 55–73], with either of these two conformations, were aligned (Fig 3A). Notably, eleven of these TRBV domains share the same C” strand conformation as TRBV7-9, whereas the TRBV domains that are not activated by SEE adopt the other conformation (Fig 3A). Clearly, the hydrogen bond pattern formed by SEE to TRBV7-9 cannot be formed to TRBV domains exhibiting the other conformation, as exemplified by TRBV19 (Fig 3B). Eight out of the eleven with the same CDR2 loop and C” strand conformation, are activated by SEE. Due to the rather broad reactivity of SEE and the common CDR2 structure of TRBVs recognized by SEE, it is likely that this SAg discriminates between TRBV domains partly based on CDR2 loop conformation (Fig 3A) [11]. However, three TRBV domains with the same CDR2 conformation are still not recognized by SEE: TRBV9, TRBV5-6 and TRBV5-8 (Fig 3A) [11]. Another important player for the TRBV specificity for SEE is the HV4 loop. It has been shown that T cells expressing the TRBV7-2*01 allele, with a Gly84b (IMGT numbering) in the HV4 loop [63], which corresponds to Gly73b in TRBV7-9, are activated by SEE, while TRBV7-2*02 with a glutamate instead of a glycine, is not activated by SEE [5]. Hence, it is likely that a large, charged amino acid in this position negatively affects the binding of SEE to TRBV. TRBV9 has an aspartate in this position [66], and thus this amino acid likely contributes to the ruling out of SEE recognition. Furthermore, TRBV9, TRBV5-6, and TRBV5-8 all have a glutamate at position 64 (IMGT numbering), in the CDR2 loop [57, 58, 66], whereas the corresponding residue in TRBV7-9 is Ala54b. This side-chain points towards residues Tyr205s and Pro206s in SEE. Thus, substituting the alanine to a glutamate would result in a negatively charged residue in a hydrophobic environment. In addition, the neighboring residue Asp207s may provide a negative charge, resulting in repulsion of a glutamate. Also, this region including both Pro206s and Asp207s, have been confirmed to be crucial for determining the TRBV specificity of SEE [74].

Bottom Line: Here, we present the structure of staphylococcal enterotoxin E (SEE) in complex with a human T cell receptor, as well as the unligated T cell receptor structure.In particular, the HV4 loop moves to circumvent steric clashes upon complex formation.In addition, a predicted ternary model of SEE in complex with both TCR and MHC class II displays intermolecular contacts between the TCR α-chain and the MHC, suggesting that the TCR α-chain is of importance for complex formation.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medical Science, Lund University, BMC C13, 22 184, Lund, Sweden.

ABSTRACT
T cells are crucial players in cell-mediated immunity. The specificity of their receptor, the T cell receptor (TCR), is central for the immune system to distinguish foreign from host antigens. Superantigens are bacterial toxins capable of inducing a toxic immune response by cross-linking the TCR and the major histocompatibility complex (MHC) class II and circumventing the antigen specificity. Here, we present the structure of staphylococcal enterotoxin E (SEE) in complex with a human T cell receptor, as well as the unligated T cell receptor structure. There are clear structural changes in the TCR loops upon superantigen binding. In particular, the HV4 loop moves to circumvent steric clashes upon complex formation. In addition, a predicted ternary model of SEE in complex with both TCR and MHC class II displays intermolecular contacts between the TCR α-chain and the MHC, suggesting that the TCR α-chain is of importance for complex formation.

No MeSH data available.


Related in: MedlinePlus