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Structural and regulatory diversity shape HLA-C protein expression levels

Author

Listed:
  • Gurman Kaur

    (MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford)

  • Stephanie Gras

    (Biomedicine Discovery Institute, Monash University
    Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University)

  • Jesse I. Mobbs

    (Biomedicine Discovery Institute, Monash University)

  • Julian P. Vivian

    (Biomedicine Discovery Institute, Monash University
    Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University)

  • Adrian Cortes

    (Oxford Centre for Neuroinflammation, John Radcliffe Hospital, University of Oxford
    Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Thomas Barber

    (Oxford Centre for Neuroinflammation, John Radcliffe Hospital, University of Oxford)

  • Subita Balaram Kuttikkatte

    (MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford)

  • Lise Torp Jensen

    (Aarhus University Hospital)

  • Kathrine E. Attfield

    (MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford)

  • Calliope A. Dendrou

    (Oxford Centre for Neuroinflammation, John Radcliffe Hospital, University of Oxford
    Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Mary Carrington

    (Cancer and Inflammation Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research
    The Ragon Institute of MGH, MIT and Harvard)

  • Gil McVean

    (Wellcome Trust Centre for Human Genetics, University of Oxford
    Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford)

  • Anthony W. Purcell

    (Biomedicine Discovery Institute, Monash University)

  • Jamie Rossjohn

    (Biomedicine Discovery Institute, Monash University
    Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University
    Institute of Infection and Immunity, Cardiff University, School of Medicine)

  • Lars Fugger

    (MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford
    Oxford Centre for Neuroinflammation, John Radcliffe Hospital, University of Oxford
    Aarhus University Hospital)

Abstract

Expression of HLA-C varies widely across individuals in an allele-specific manner. This variation in expression can influence efficacy of the immune response, as shown for infectious and autoimmune diseases. MicroRNA binding partially influences differential HLA-C expression, but the additional contributing factors have remained undetermined. Here we use functional and structural analyses to demonstrate that HLA-C expression is modulated not just at the RNA level, but also at the protein level. Specifically, we show that variation in exons 2 and 3, which encode the α1/α2 domains, drives differential expression of HLA-C allomorphs at the cell surface by influencing the structure of the peptide-binding cleft and the diversity of peptides bound by the HLA-C molecules. Together with a phylogenetic analysis, these results highlight the diversity and long-term balancing selection of regulatory factors that modulate HLA-C expression.

Suggested Citation

  • Gurman Kaur & Stephanie Gras & Jesse I. Mobbs & Julian P. Vivian & Adrian Cortes & Thomas Barber & Subita Balaram Kuttikkatte & Lise Torp Jensen & Kathrine E. Attfield & Calliope A. Dendrou & Mary Car, 2017. "Structural and regulatory diversity shape HLA-C protein expression levels," Nature Communications, Nature, vol. 8(1), pages 1-12, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15924
    DOI: 10.1038/ncomms15924
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    Cited by:

    1. Jiaqi Ma & Cory M. Ayres & Chad A. Brambley & Smita S. Chandran & Tatiana J. Rosales & W. W. J. Gihan Perera & Bassant Eldaly & William T. Murray & Steven A. Corcelli & Evgenii L. Kovrigin & Christoph, 2025. "Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity," Nature Communications, Nature, vol. 16(1), pages 1-21, December.

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