Appreciating the Complexity of MHC Class II Peptide Binding: Lysozyme Peptide and I‐A<sup>k</sup>

Nelson, Christopher A.; Viner, Nicholas J.; Unanue, Emil R.

doi:10.1111/j.1600-065x.1996.tb00704.x

Cited by 46 publications

(40 citation statements)

References 53 publications

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“…This assignment places N44, V47, E49, S50, and A52 at the respective P1, P4, P6, P7, and P9 positions in conformity with the HEL/I-A k crystal structure (16). These proposed anchors also match allowable residues in the established I-A k binding motif (20), and they further predicted T45, F46, H48, and L51 to be the P2, P3, P5, and P8 TCR contacts, respectively. Using this designation, these RN 42-56 amino acid side chains are shown in their predicted conformation on the peptide backbone from HEL/I-A k crystal structure ( Fig.…”

Section: Four Amino Acids Of Rn 42-56 Bound To I-a K Can Contact a Tcrmentioning

confidence: 94%

“…A putative binding register was assigned for the peptide based on a previous mapping study of this epitope on I-A k (18) and the presence of a single N that makes a suitable P1 anchor (19,20). This assignment places N44, V47, E49, S50, and A52 at the respective P1, P4, P6, P7, and P9 positions in conformity with the HEL/I-A k crystal structure (16).…”

Section: Four Amino Acids Of Rn 42-56 Bound To I-a K Can Contact a Tcrmentioning

confidence: 99%

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Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

Basu

Horváth

Matsumoto

et al. 2000

The Journal of Immunology

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KRN TCR transgenic T cells recognize two self-MHC molecules: a foreign peptide, bovine RNase 42–56, on I-Ak and an autoantigen, glucose-6-phosphate isomerase 282–294, on I-Ag7. Because the latter recognition event initiates a disease closely resembling human rheumatoid arthritis, we investigated the structural basis of this pathogenic TCR’s dual specificity. While peptide recognition is altered to a minor degree between the MHC molecules, we show that the receptor’s cross-reactivity critically depends upon a TCR contact residue completely conserved in the foreign and self peptides. Further, the altered recognition of peptide derives from discrete differences on the MHC recognition surfaces and not the disparate binding grooves. This work provides a detailed structural comparison of an autoreactive TCR’s interactions with naturally occurring peptides on distinct MHC molecules. The capacity to interact with multiple self-MHCs in this manner increases the number of potentially pathogenic self-interactions available to a T cell.

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Section: Four Amino Acids Of Rn 42-56 Bound To I-a K Can Contact a Tcrmentioning

confidence: 94%

Section: Four Amino Acids Of Rn 42-56 Bound To I-a K Can Contact a Tcrmentioning

confidence: 99%

Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

Basu

Horváth

Matsumoto

et al. 2000

The Journal of Immunology

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“…4 and unpublished results), nor does weakening of pocket interactions make a peptide more dependent on hydrogen bonds (unpublished results). Secondly, we have initiated studies with the I-A k molecule, which is thought to have strong pocket interactions with its bound peptides (7,25). Our analyses thus far involving intracellular trafficking studies suggest that, like the I-A d molecule, I-A k molecules with hydrogen bond losses at ␤-82 or ␤-81 have a severely compromised ability to stably acquire peptide (unpublished results).…”

Section: Discussionmentioning

confidence: 99%

Energetic asymmetry among hydrogen bonds in MHC class II⋅peptide complexes

McFarland

Katz

Beeson

et al. 2001

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

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Comparison of crystallized MHC class II⅐peptide complexes has revealed that, in addition to pocket interactions involving the peptide side chains, peptide binding to MHC class II molecules is characterized by a series of hydrogen bonds between genetically conserved amino acid residues in the class II molecule and the main chain of the peptide. Many class II⅐peptide structures have two sets of symmetrical hydrogen bonds at the opposite ends of the class II antigen-binding groove (␤-His-81, ␤-Asn-82 vs. ␣-His-68, ␣-Asn-69). In this study, we alter these peripheral hydrogen bonds and measure the apparent contribution of each to the kinetic stability of peptide⅐class II complexes. Single conservative amino substitutions were made in the I-A d protein to eliminate participation as a hydrogen bonding residue, and the kinetic stability of a diverse set of peptides bound to the substituted I-A d proteins was measured. Although each hydrogen bond does contribute to peptide binding, our results point to the striking conclusion that those hydrogen bonds localized to the amino terminus of the peptide contribute profoundly and disproportionately to the stability of peptide interactions with I-A d . We suggest that the peripheral hydrogen bonds at the amino terminus of the bound peptide that are conserved in all class II⅐peptide crystal structures solved thus far form a cooperative network that critically regulates peptide dissociation from the class II molecule.M ajor histocompatibility complex (MHC) class II molecules are composed of two noncovalently associated, polymorphic transmembrane proteins, termed ␣ and ␤, of approximate molecular mass of 33 kDa and 28 kDa, respectively. They interact with T cell receptors to provoke an antigen-specific CD4 ϩ T cell response. Crystal structures of class II molecules have provided insight into the structural elements that control interactions with peptide. Both polymorphic and genetically conserved amino acid residues make contacts with the bound peptide (1-7). Most of the polymorphic residues face the interior of the peptide-binding groove, and thus contribute to allele-dependent peptide binding. Similar to what has been observed in class I molecules, MHC class II molecules appear to have ''pockets'' that are capable of binding to peptide side chains. In addition to these pocket interactions, MHC class II molecules bind peptide through a series of hydrogen bonds between genetically conserved amino acid residues in the class II molecule and the main chain of the peptide. These conserved residues bind at relatively regular intervals throughout the length of the peptide, and apparently stabilize the peptide in a fairly fixed polyproline type II conformation throughout the length of the peptide-binding pocket (3).One striking aspect of class II⅐peptide structures noted in murine complexes (6, 7) are two sets of symmetrical hydrogen bonds at the opposite ends of the binding pocket (Fig. 1). The hydrogen bonds contributed by ␤-His-81 and ␤-Asn-82 are localized to the bound peptide's amino...

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“…This peptide binds with high affinity to H2-A k dimers. 31 The minimal peptide recognized by the 3A9 T hybridoma is the HEL sequence aa 52-61. 31 Further truncation of this sequence abolishes binding to H2-A k and stimulation of 3A9 T cells.…”

Section: Resultsmentioning

confidence: 99%

“…31 The minimal peptide recognized by the 3A9 T hybridoma is the HEL sequence aa 52-61. 31 Further truncation of this sequence abolishes binding to H2-A k and stimulation of 3A9 T cells. This sequence was introduced into Ii by cloning the oligonucleotides encoding aa 52-61 of HEL into the DraIII site directly beyond the coding sequence of the Ii cDNA.…”

Section: Resultsmentioning

confidence: 99%

C-terminal extension of the MHC class II-associated invariant chain by an antigenic sequence triggers activation of naive T cells

1999

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In vitro and in vivo activation of T cells was investigated T hybridoma cells. Nonprofessional APC expressing with invariant chain-antigen fusion protein. The CD4 T cell recombinant Ii HEL and H2-A k are also able to activate epitope amino acid 52-61 of hen egg lysozyme (HEL) was naive T cells from 3A9 TCR transgenic mice, a result not attached to the C-terminal end of invariant chain (Ii).achieved with peptide pulsed APC. To elicit an in vivo Expression of this recombinant Ii HEL directs the T cell immune response dendritic cells (DC) were transfected epitope to the class II processing pathway. Class II molwith rIi HEL cDNA: following immunization of CBA mice ecules of transfected antigen presenting cells (APC) are with transfected DC, a primary T cell response against the charged with this HEL epitope. The endogenously provided HEL epitope was induced. Thus the procedure described epitope competes with processing and presentation of here could be used to introduce antigens into the class II exogenously added antigen. APC expressing recombinant processing pathway and to elicit T cell activation both in Ii HEL stimulate a maximal IL-2 response of HEL-specific vitro and in vivo.

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Appreciating the Complexity of MHC Class II Peptide Binding: Lysozyme Peptide and I‐A^k

Abstract: Initial attempts to characterize the peptide sequences recognized by T cells focused on the definition of minimal determinants within protein antigens, and many MHC class II restricted T cells could recognize synthetic peplides as short as 8 or

Cited by 46 publications

References 53 publications

Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

Energetic asymmetry among hydrogen bonds in MHC class II⋅peptide complexes

C-terminal extension of the MHC class II-associated invariant chain by an antigenic sequence triggers activation of naive T cells

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Appreciating the Complexity of MHC Class II Peptide Binding: Lysozyme Peptide and I‐Ak

Abstract: Initial attempts to characterize the peptide sequences recognized by T cells focused on the definition of minimal determinants within protein antigens, and many MHC class II restricted T cells could recognize synthetic peplides as short as 8 or

Cited by 46 publications

References 53 publications

Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

Energetic asymmetry among hydrogen bonds in MHC class II⋅peptide complexes

C-terminal extension of the MHC class II-associated invariant chain by an antigenic sequence triggers activation of naive T cells

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Appreciating the Complexity of MHC Class II Peptide Binding: Lysozyme Peptide and I‐A^k