High Resolution Structures of Highly Bulged Viral Epitopes Bound to Major Histocompatibility Complex Class I

Tynan, Fleur Elizabeth; Borg, Natalie A.; Miles, John J.; Beddoe, Travis; Elhassen, Diah; Silins, Sharon L.; Zuylen, Wendy J. van; Purcell, Anthony W.; Kjer‐Nielsen, Lars; McCluskey, James; Burrows, Scott R.; Rossjohn, Jamie

doi:10.1074/jbc.m503060200

Cited by 151 publications

(170 citation statements)

References 81 publications

(69 reference statements)

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“…Additionally, two other CTL clones specific for this 13-mer peptide (SB9 and CA5) with different TCRs (14,16,23) were insensitive to the restriction triad mutations (Fig. S2).…”

Section: Resultsmentioning

confidence: 99%

“…We generated a series of single (Q65A, T69A, and Q155A) and triple (Q65, T69, and Q155→A) alanine mutations within the MHC-I and analyzed their effect on TCR binding using surface plasmon resonance (SPR) in two different systems (LC13 TCR-HLA-B*0801 and SB27 TCR-HLA-B*3508) (16,17) (Fig. 1 and Table S2).…”

Section: Resultsmentioning

confidence: 99%

“…Data were processed using standard crystal- (Table S3). The structure of HLA-B*3508-AAA LPEP was determined by molecular replacement using the HLA-B*3508 LPEP structure as the search model (16). For the SB27-HLA-B*3508-AAA LPEP complex, the crystals belonged to the space group P2 1 with four complexes in the asymmetric unit.…”

Section: Methodsmentioning

confidence: 99%

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Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability

Burrows

Chen

Archbold

et al. 2010

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

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107

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αβ T cell receptors (TCRs) are genetically restricted to corecognize peptide antigens bound to self-major histocompatibility complex (pMHC) molecules; however, the basis for this MHC specificity remains unclear. Despite the current dogma, evaluation of the TCR-pMHC-I structural database shows that the nongermline-encoded complementaritydetermining region (CDR)-3 loops often contact the MHC-I, and the germline-encoded CDR1 and -2 loops frequently participate in peptide-mediated interactions. Nevertheless, different TCRs adopt a roughly conserved docking mode over the pMHC-I, in which three MHC-I residues (65, 69, and 155) are invariably contacted by the TCR in one way or another. Nonetheless, the impact of mutations at these three positions, either individually or together, was not uniformly detrimental to TCR recognition of pHLA-B*0801 or pHLA-B*3508. Moreover, when TCR-pMHC-I recognition was impaired, this could be partially restored by expression of the CD8 coreceptor. The structure of a TCR-pMHC-I complex in which these three (65, 69, and 155) MHC-I positions were all mutated resulted in shifting of the TCR footprint relative to the cognate complex and formation of compensatory interactions. Collectively, our findings reveal the inherent adaptability of the TCR in maintaining peptide recognition while accommodating changes to the central docking site on the pMHC-I.MHC restriction | T cell recognition | structural immunology | immunogenetics D uring thymic selection αβ T cell receptors (TCRs) are selected for weak reactivity with one or more self-peptides in complex with self-MHC (major histocompatibility complex), resulting in mature T cells being restricted to recognize processed peptides only when they are presented by self-MHC molecules (1). The exquisite specificity of TCR-pMHC binding must address the highly polymorphic nature of the MHC and variable peptide cargo. The antigen-recognition site of the TCR is made up of six complementarity-determining regions (CDRs), three each from the α and β chains (2). Currently, it is postulated that the CDR1 and 2 loops underpin the specificity or "bias" toward the MHC, whereas the CDR3 loops recognize the diverse range of bound peptides (3-5). Recent studies support the view that the T cell repertoire is intrinsically biased toward the MHC through contacts mediated by conserved TCR Vα and Vβ residues (6). However, the factors governing MHC restriction, a central paradigm of antigen-specific T cell immunity, remain unclear.Presumably as a consequence of the polymorphic pMHC landscape, and the inherent diversity of the responding T cell repertoire, structural studies have shown that the TCR engages the pMHC-I and pMHC-II surfaces in a range of different docking modes (2). Nevertheless, conserved pairwise interactions between closely related Vβ8.2 + TCRs and pMHC-II molecules were identified, leading to the concept that there are defined interaction "motifs" or "codons" between the Vα and/or Vβ domains of a TCR and a given MHC allotype (3,(6)(7)(8). Central to the "int...

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“…Additionally, two other CTL clones specific for this 13-mer peptide (SB9 and CA5) with different TCRs (14,16,23) were insensitive to the restriction triad mutations (Fig. S2).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability

Burrows

Chen

Archbold

et al. 2010

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

Self Cite

107

122

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“…Some longer HLA-I-restricted peptides have been described, but on account of the conserved polar interaction network with the N-and C-termini in the P1 and P longer peptides are canonically accommodated in the groove by adopting a 'bulged' conformation, where the central portion of the peptide epitope projects from the groove 8,9,10 . The T-cell receptor (TCR) binds these bulged regions of the peptide whilst simultaneously contacting the HLA-I molecule.…”

Section: Introductionmentioning

confidence: 99%

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

Pymm

Illing

Ramarathinam

et al. 2017

Nat Struct Mol Biol

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“…This binding mode leaves the upward-pointing peptide side chains available for direct interaction with the TCR (40). Longer peptides can either bind by extension at the C terminus (41) or, due to the fixing of their termini, bulge out of the binding groove, providing additional surface area for TCR recognition (42,43). Thus, the bound peptide is more accessible for TCR inspection in MHC-I due to its ability to bulge out of the groove (40).…”

Section: Molecular Basis Of Mhc-i/tcr Interactionmentioning

confidence: 99%

Manipulation of MHC-I/TCR Interaction for Immune Therapy

Liu

Gao

2008

Cell Mol Immunol

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High Resolution Structures of Highly Bulged Viral Epitopes Bound to Major Histocompatibility Complex Class I

Cited by 151 publications

References 81 publications

Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability

Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

Manipulation of MHC-I/TCR Interaction for Immune Therapy

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