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Structure and Peptidomes of Swine MHC Class I with Long Peptides Reveal the Cross-Species Characteristics of the Novel N-Terminal Extension Presentation Mode

Xiaohui Wei, Song Wang, Suqiu Wang, Xiaoli Xie and Nianzhi Zhang
J Immunol January 15, 2022, 208 (2) 480-491; DOI: https://doi.org/10.4049/jimmunol.2001207
Xiaohui Wei
*Department of Microbiology and Immunology, College of Veterinary Medicine, China Agricultural University, Beijing, China; and
†NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
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Song Wang
*Department of Microbiology and Immunology, College of Veterinary Medicine, China Agricultural University, Beijing, China; and
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Suqiu Wang
*Department of Microbiology and Immunology, College of Veterinary Medicine, China Agricultural University, Beijing, China; and
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Xiaoli Xie
*Department of Microbiology and Immunology, College of Veterinary Medicine, China Agricultural University, Beijing, China; and
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Nianzhi Zhang
*Department of Microbiology and Immunology, College of Veterinary Medicine, China Agricultural University, Beijing, China; and
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Key Points

  • There are cross-species features of the N-terminal extension of peptides bound by MHC class I.

  • The polymorphic A pocket residues have pros and cons to the peptide extension.

  • The N-terminal extension of the peptide does not exceed three residues.

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Abstract

Antigenic peptide presentation by the MHC is essential for activating T cells. The current view is that the peptide termini are tethered within the closed Ag-binding groove of MHC class I (MHC-I). Recently, the N-terminal extension mode of peptide presentation has been observed in human MHC-I (HLA-I). In this study, we found that the N terminus of the long peptide can extend beyond the groove of swine MHC-I (SLA-1*0401), confirming that this phenomenon can occur across species. Removal of the N-terminal extra (P-1) residue of the RW12 peptide significantly reduced the folding efficiency of the complex, but truncation of the second half of the peptide did not. Consistent with previous reports, the second (P1) residue of the peptide is twisted, and its side chain is inserted into the A pocket to form two hydrogen bonds with polymorphic E63 and conserved Y159. Mutations of E63 disrupt the binding of the peptide, indicating that E63 is necessary for this peptide-binding mode. Compared with W167, which exists in most MHC-Is, SLA-I–specific S167 ensures an open N-terminal groove of SLA-1*0401, enabling the P-1 residue to extend from the groove. In this MHC class II–like peptide-binding mode, the A pocket is restrictive to the P1 residue and is affected by the polymorphic residues. The peptidomes and refolding data indicated that the open N-terminal groove of SLA-1*0401 allows one to three residues to extend out of the Ag-binding groove. These cross-species comparisons can help us better understand the characteristics of this N-terminal extension presentation mode.

Footnotes

  • This work was supported by grants from the National Natural Science Foundation of China (31830097 and 31201887), the Natural Science Foundation of Beijing Municipality (6182029), the Major Science and Technology Project of Liaoning Province (2020JH1/10200003), the 2115 Talent Development Program of China Agricultural University, and the National Key Research and Development Program of China (2021YFD1800100).

  • N.Z. designed the study and supervised the project; X.W. performed the experiments and analyzed the data; Song Wang and Suqiu Wang assisted in the experiments; X.W. and Suqiu Wang solved the structure; X.X. provided guidance on data analysis; X.W. and N.Z. wrote the paper.

  • The coordinate and structure factors presented in this article have been submitted to the Protein Data Bank under accession number 6LF8 and the mass spectrometry proteomics data have been submitted to the ProteomeXchange Consortium under accession number PXD020818.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    CD
    circular dichroism
    MHC-I
    MHC class I
    MHC-II
    MHC class II
    MS
    mass spectrometry
    PDB
    Protein Data Bank
    sβ2m
    swine β-2-microglobulin
    TFA
    trifluoroacetic acid
    Tm
    midpoint transition temperature

  • Received October 26, 2020.
  • Accepted November 5, 2021.
  • Copyright © 2022 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (2)
The Journal of Immunology
Vol. 208, Issue 2
15 Jan 2022
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Structure and Peptidomes of Swine MHC Class I with Long Peptides Reveal the Cross-Species Characteristics of the Novel N-Terminal Extension Presentation Mode
Xiaohui Wei, Song Wang, Suqiu Wang, Xiaoli Xie, Nianzhi Zhang
The Journal of Immunology January 15, 2022, 208 (2) 480-491; DOI: 10.4049/jimmunol.2001207

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Structure and Peptidomes of Swine MHC Class I with Long Peptides Reveal the Cross-Species Characteristics of the Novel N-Terminal Extension Presentation Mode
Xiaohui Wei, Song Wang, Suqiu Wang, Xiaoli Xie, Nianzhi Zhang
The Journal of Immunology January 15, 2022, 208 (2) 480-491; DOI: 10.4049/jimmunol.2001207
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