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Glycoproteomic landscape and structural dynamics of TIM family immune checkpoints enabled by mucinase SmE

Author

Listed:
  • Joann Chongsaritsinsuk

    (Yale University)

  • Alexandra D. Steigmeyer

    (Yale University)

  • Keira E. Mahoney

    (Yale University)

  • Mia A. Rosenfeld

    (University of California, San Diego)

  • Taryn M. Lucas

    (Yale University)

  • Courtney M. Smith

    (Yale University School of Medicine)

  • Alice Li

    (Yale University School of Medicine)

  • Deniz Ince

    (Yale University)

  • Fiona L. Kearns

    (University of California, San Diego)

  • Alexandria S. Battison

    (Yale University)

  • Marie A. Hollenhorst

    (Stanford University
    Stanford University
    Stanford University)

  • D. Judy Shon

    (Stanford University)

  • Katherine H. Tiemeyer

    (Stanford University)

  • Victor Attah

    (Yale University)

  • Catherine Kwon

    (Yale University)

  • Carolyn R. Bertozzi

    (Stanford University
    Stanford University)

  • Michael J. Ferracane

    (University of Redlands)

  • Mark A. Lemmon

    (Yale University School of Medicine)

  • Rommie E. Amaro

    (University of California, San Diego
    University of California, San Diego)

  • Stacy A. Malaker

    (Yale University)

Abstract

Mucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of biological functions. In particular, the T cell immunoglobulin and mucin-domain containing family of proteins (TIM-1, -3, -4) decorate immune cells and act as key regulators in cellular immunity. However, their dense O-glycosylation remains enigmatic, primarily due to the challenges associated with studying mucin domains. Here, we demonstrate that the mucinase SmE has a unique ability to cleave at residues bearing very complex glycans. SmE enables improved mass spectrometric analysis of several mucins, including the entire TIM family. With this information in-hand, we perform molecular dynamics (MD) simulations of TIM-3 and -4 to understand how glycosylation affects structural features of these proteins. Finally, we use these models to investigate the functional relevance of glycosylation for TIM-3 function and ligand binding. Overall, we present a powerful workflow to better understand the detailed molecular structures and functions of the mucinome.

Suggested Citation

  • Joann Chongsaritsinsuk & Alexandra D. Steigmeyer & Keira E. Mahoney & Mia A. Rosenfeld & Taryn M. Lucas & Courtney M. Smith & Alice Li & Deniz Ince & Fiona L. Kearns & Alexandria S. Battison & Marie A, 2023. "Glycoproteomic landscape and structural dynamics of TIM family immune checkpoints enabled by mucinase SmE," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41756-y
    DOI: 10.1038/s41467-023-41756-y
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