Peptide binding to MHC class I is determined by individual pockets in the binding groove

T. E. Johansen, K. McCullough, B. Catipovic, X. M. Su, Mario L Amzel, Jonathan P Schneck

Research output: Contribution to journalArticle

Abstract

H-2K(b) and HLA-A2 are MHC4 class I molecules with a similar overall structure. Important differences between these two class I molecules reside in the structure of the individual pockets in the antigenic-peptide-binding groove. H-2K(b), which has a deep C pocket, binds specifically peptides with a tyrosine or a phenylalanine at position 5. In contrast, HLA-A2 has a shallow C pocket, which cannot accommodate large side chains at position 5. Site-directed mutagenesis was used to generate a chimera between the murine H-2K(b) and the human HLA-A2 [H-2K(b)/HLA-A2(C')]. The structure of this chimera is similar to H-2K(b) except for the region around the deep C pocket, where residues at positions 9, 97 and 99 were substituted with those bulkier residues from HLA-A2. Peptide binding between this chimera and H-2K(b)- binding peptides [VSV (52-59), OVA (257-264), and MCMV pp89 (168-176)], revealed that the deep C pocket of H-2K(b) was crucial for high-affinity binding. While a peptide, VSV (52-59), was found to bind with severalfold lower 'affinity' to H-2K(b)/HLA-A2(C') than to the wild-type H-2K(b), a VSV analogue with the tyrosine in position 5 (Tyr5) substituted with an alanine was found to bind with a similar 'affinity' to both MHC class I molecules. Computer-aided modelling of the H-2K(b)/HLA-A2(C') complex indicates that the VSV (52-59) peptide probably binds to the chimeric MHC molecule with the peptide side chain of anchor residue Tyr5 pointing away from the groove. These results confirm a role of the individual pockets in determining peptide-binding affinity and specificity and suggest that this may be accomplished by changes in side-chain orientation.

Original languageEnglish (US)
Pages (from-to)137-146
Number of pages10
JournalScandinavian Journal of Immunology
Volume46
Issue number2
StatePublished - 1997

Fingerprint

HLA-A2 Antigen
Peptides
HLA-C Antigens
Tyrosine
MHC binding peptide
Site-Directed Mutagenesis
Phenylalanine
Alanine

ASJC Scopus subject areas

  • Immunology

Cite this

Peptide binding to MHC class I is determined by individual pockets in the binding groove. / Johansen, T. E.; McCullough, K.; Catipovic, B.; Su, X. M.; Amzel, Mario L; Schneck, Jonathan P.

In: Scandinavian Journal of Immunology, Vol. 46, No. 2, 1997, p. 137-146.

Research output: Contribution to journalArticle

@article{e82ec5c4ce9b414db82e5860ac327774,
title = "Peptide binding to MHC class I is determined by individual pockets in the binding groove",
abstract = "H-2K(b) and HLA-A2 are MHC4 class I molecules with a similar overall structure. Important differences between these two class I molecules reside in the structure of the individual pockets in the antigenic-peptide-binding groove. H-2K(b), which has a deep C pocket, binds specifically peptides with a tyrosine or a phenylalanine at position 5. In contrast, HLA-A2 has a shallow C pocket, which cannot accommodate large side chains at position 5. Site-directed mutagenesis was used to generate a chimera between the murine H-2K(b) and the human HLA-A2 [H-2K(b)/HLA-A2(C')]. The structure of this chimera is similar to H-2K(b) except for the region around the deep C pocket, where residues at positions 9, 97 and 99 were substituted with those bulkier residues from HLA-A2. Peptide binding between this chimera and H-2K(b)- binding peptides [VSV (52-59), OVA (257-264), and MCMV pp89 (168-176)], revealed that the deep C pocket of H-2K(b) was crucial for high-affinity binding. While a peptide, VSV (52-59), was found to bind with severalfold lower 'affinity' to H-2K(b)/HLA-A2(C') than to the wild-type H-2K(b), a VSV analogue with the tyrosine in position 5 (Tyr5) substituted with an alanine was found to bind with a similar 'affinity' to both MHC class I molecules. Computer-aided modelling of the H-2K(b)/HLA-A2(C') complex indicates that the VSV (52-59) peptide probably binds to the chimeric MHC molecule with the peptide side chain of anchor residue Tyr5 pointing away from the groove. These results confirm a role of the individual pockets in determining peptide-binding affinity and specificity and suggest that this may be accomplished by changes in side-chain orientation.",
author = "Johansen, {T. E.} and K. McCullough and B. Catipovic and Su, {X. M.} and Amzel, {Mario L} and Schneck, {Jonathan P}",
year = "1997",
language = "English (US)",
volume = "46",
pages = "137--146",
journal = "Scandinavian Journal of Immunology",
issn = "0300-9475",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Peptide binding to MHC class I is determined by individual pockets in the binding groove

AU - Johansen, T. E.

AU - McCullough, K.

AU - Catipovic, B.

AU - Su, X. M.

AU - Amzel, Mario L

AU - Schneck, Jonathan P

PY - 1997

Y1 - 1997

N2 - H-2K(b) and HLA-A2 are MHC4 class I molecules with a similar overall structure. Important differences between these two class I molecules reside in the structure of the individual pockets in the antigenic-peptide-binding groove. H-2K(b), which has a deep C pocket, binds specifically peptides with a tyrosine or a phenylalanine at position 5. In contrast, HLA-A2 has a shallow C pocket, which cannot accommodate large side chains at position 5. Site-directed mutagenesis was used to generate a chimera between the murine H-2K(b) and the human HLA-A2 [H-2K(b)/HLA-A2(C')]. The structure of this chimera is similar to H-2K(b) except for the region around the deep C pocket, where residues at positions 9, 97 and 99 were substituted with those bulkier residues from HLA-A2. Peptide binding between this chimera and H-2K(b)- binding peptides [VSV (52-59), OVA (257-264), and MCMV pp89 (168-176)], revealed that the deep C pocket of H-2K(b) was crucial for high-affinity binding. While a peptide, VSV (52-59), was found to bind with severalfold lower 'affinity' to H-2K(b)/HLA-A2(C') than to the wild-type H-2K(b), a VSV analogue with the tyrosine in position 5 (Tyr5) substituted with an alanine was found to bind with a similar 'affinity' to both MHC class I molecules. Computer-aided modelling of the H-2K(b)/HLA-A2(C') complex indicates that the VSV (52-59) peptide probably binds to the chimeric MHC molecule with the peptide side chain of anchor residue Tyr5 pointing away from the groove. These results confirm a role of the individual pockets in determining peptide-binding affinity and specificity and suggest that this may be accomplished by changes in side-chain orientation.

AB - H-2K(b) and HLA-A2 are MHC4 class I molecules with a similar overall structure. Important differences between these two class I molecules reside in the structure of the individual pockets in the antigenic-peptide-binding groove. H-2K(b), which has a deep C pocket, binds specifically peptides with a tyrosine or a phenylalanine at position 5. In contrast, HLA-A2 has a shallow C pocket, which cannot accommodate large side chains at position 5. Site-directed mutagenesis was used to generate a chimera between the murine H-2K(b) and the human HLA-A2 [H-2K(b)/HLA-A2(C')]. The structure of this chimera is similar to H-2K(b) except for the region around the deep C pocket, where residues at positions 9, 97 and 99 were substituted with those bulkier residues from HLA-A2. Peptide binding between this chimera and H-2K(b)- binding peptides [VSV (52-59), OVA (257-264), and MCMV pp89 (168-176)], revealed that the deep C pocket of H-2K(b) was crucial for high-affinity binding. While a peptide, VSV (52-59), was found to bind with severalfold lower 'affinity' to H-2K(b)/HLA-A2(C') than to the wild-type H-2K(b), a VSV analogue with the tyrosine in position 5 (Tyr5) substituted with an alanine was found to bind with a similar 'affinity' to both MHC class I molecules. Computer-aided modelling of the H-2K(b)/HLA-A2(C') complex indicates that the VSV (52-59) peptide probably binds to the chimeric MHC molecule with the peptide side chain of anchor residue Tyr5 pointing away from the groove. These results confirm a role of the individual pockets in determining peptide-binding affinity and specificity and suggest that this may be accomplished by changes in side-chain orientation.

UR - http://www.scopus.com/inward/record.url?scp=0030802706&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030802706&partnerID=8YFLogxK

M3 - Article

VL - 46

SP - 137

EP - 146

JO - Scandinavian Journal of Immunology

JF - Scandinavian Journal of Immunology

SN - 0300-9475

IS - 2

ER -