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An atlas of O-linked glycosylation on peptide hormones reveals diverse biological roles

Author

Listed:
  • Thomas D. Madsen

    (University of Copenhagen)

  • Lasse H. Hansen

    (University of Copenhagen
    Rigshospitalet, University of Copenhagen)

  • John Hintze

    (University of Copenhagen)

  • Zilu Ye

    (University of Copenhagen)

  • Shifa Jebari

    (Universidad del País Vasco)

  • Daniel B. Andersen

    (Faculty of Health and Medical Sciences, University of Copenhagen
    University of Copenhagen)

  • Hiren J. Joshi

    (University of Copenhagen)

  • Tongzhong Ju

    (U.S. Food and Drug Administration)

  • Jens P. Goetze

    (Rigshospitalet, University of Copenhagen
    Faculty of Health and Medical Sciences, University of Copenhagen)

  • Cesar Martin

    (U.S. Food and Drug Administration)

  • Mette M. Rosenkilde

    (Faculty of Health and Medical Sciences, University of Copenhagen)

  • Jens J. Holst

    (Faculty of Health and Medical Sciences, University of Copenhagen
    University of Copenhagen)

  • Rune E. Kuhre

    (Faculty of Health and Medical Sciences, University of Copenhagen
    University of Copenhagen)

  • Christoffer K. Goth

    (University of Copenhagen)

  • Sergey Y. Vakhrushev

    (University of Copenhagen)

  • Katrine T. Schjoldager

    (University of Copenhagen)

Abstract

Peptide hormones and neuropeptides encompass a large class of bioactive peptides that regulate physiological processes like anxiety, blood glucose, appetite, inflammation and blood pressure. Here, we execute a focused discovery strategy to provide an extensive map of O-glycans on peptide hormones. We find that almost one third of the 279 classified peptide hormones carry O-glycans. Many of the identified O-glycosites are conserved and are predicted to serve roles in proprotein processing, receptor interaction, biodistribution and biostability. We demonstrate that O-glycans positioned within the receptor binding motifs of members of the neuropeptide Y and glucagon families modulate receptor activation properties and substantially extend peptide half-lives. Our study highlights the importance of O-glycosylation in the biology of peptide hormones, and our map of O-glycosites in this large class of biomolecules serves as a discovery platform for an important class of molecules with potential opportunities for drug designs.

Suggested Citation

  • Thomas D. Madsen & Lasse H. Hansen & John Hintze & Zilu Ye & Shifa Jebari & Daniel B. Andersen & Hiren J. Joshi & Tongzhong Ju & Jens P. Goetze & Cesar Martin & Mette M. Rosenkilde & Jens J. Holst & R, 2020. "An atlas of O-linked glycosylation on peptide hormones reveals diverse biological roles," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17473-1
    DOI: 10.1038/s41467-020-17473-1
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    Cited by:

    1. Ho Yan Yeung & Iris Bea L. Ramiro & Daniel B. Andersen & Thomas Lund Koch & Alexander Hamilton & Walden E. Bjørn-Yoshimoto & Samuel Espino & Sergey Y. Vakhrushev & Kasper B. Pedersen & Noortje Haan & , 2024. "Fish-hunting cone snail disrupts prey’s glucose homeostasis with weaponized mimetics of somatostatin and insulin," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Christian T. Madsen & Jan C. Refsgaard & Felix G. Teufel & Sonny K. Kjærulff & Zhe Wang & Guangjun Meng & Carsten Jessen & Petteri Heljo & Qunfeng Jiang & Xin Zhao & Bo Wu & Xueping Zhou & Yang Tang &, 2022. "Combining mass spectrometry and machine learning to discover bioactive peptides," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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