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Structural and mechanistic insights into the cleavage of clustered O-glycan patches-containing glycoproteins by mucinases of the human gut

Author

Listed:
  • Víctor Taleb

    (University of Zaragoza)

  • Qinghua Liao

    (Universitat de Barcelona)

  • Yoshiki Narimatsu

    (University of Copenhagen)

  • Ana García-García

    (University of Zaragoza)

  • Ismael Compañón

    (Centro de Investigación en Síntesis Química)

  • Rafael Junqueira Borges

    (Universidade Estadual Paulista (UNESP))

  • Andrés Manuel González-Ramírez

    (University of Zaragoza)

  • Francisco Corzana

    (Centro de Investigación en Síntesis Química)

  • Henrik Clausen

    (University of Copenhagen)

  • Carme Rovira

    (Universitat de Barcelona
    Institució Catalana de Recerca i Estudis Avancats (ICREA))

  • Ramon Hurtado-Guerrero

    (University of Zaragoza
    University of Copenhagen
    Fundación ARAID)

Abstract

Mucinases of human gut bacteria cleave peptide bonds in mucins strictly depending on the presence of neighboring O-glycans. The Akkermansia muciniphila AM0627 mucinase cleaves specifically in between contiguous (bis) O-glycans of defined truncated structures, suggesting that this enzyme may recognize clustered O-glycan patches. Here, we report the structure and molecular mechanism of AM0627 in complex with a glycopeptide containing a bis-T (Galβ1-3GalNAcα1-O-Ser/Thr) O-glycan, revealing that AM0627 recognizes both the sugar moieties and the peptide sequence. AM0627 exhibits preference for bis-T over bis-Tn (GalNAcα1-O-Ser/Thr) O-glycopeptide substrates, with the first GalNAc residue being essential for cleavage. AM0627 follows a mechanism relying on a nucleophilic water molecule and a catalytic base Glu residue. Structural comparison among mucinases identifies a conserved Tyr engaged in sugar-π interactions in both AM0627 and the Bacteroides thetaiotaomicron BT4244 mucinase as responsible for the common activity of these two mucinases with bis-T/Tn substrates. Our work illustrates how mucinases through tremendous flexibility adapt to the diversity in distribution and patterns of O-glycans on mucins.

Suggested Citation

  • Víctor Taleb & Qinghua Liao & Yoshiki Narimatsu & Ana García-García & Ismael Compañón & Rafael Junqueira Borges & Andrés Manuel González-Ramírez & Francisco Corzana & Henrik Clausen & Carme Rovira & R, 2022. "Structural and mechanistic insights into the cleavage of clustered O-glycan patches-containing glycoproteins by mucinases of the human gut," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32021-9
    DOI: 10.1038/s41467-022-32021-9
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    References listed on IDEAS

    as
    1. Beatriz Trastoy & Andreas Naegeli & Itxaso Anso & Jonathan Sjögren & Marcelo E. Guerin, 2020. "Structural basis of mammalian mucin processing by the human gut O-glycopeptidase OgpA from Akkermansia muciniphila," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    2. Andrés Manuel González-Ramírez & Ana Sofia Grosso & Zhang Yang & Ismael Compañón & Helena Coelho & Yoshiki Narimatsu & Henrik Clausen & Filipa Marcelo & Francisco Corzana & Ramon Hurtado-Guerrero, 2022. "Structural basis for the synthesis of the core 1 structure by C1GalT1," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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    Cited by:

    1. 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.
    2. Janneke Elzinga & Yoshiki Narimatsu & Noortje Haan & Henrik Clausen & Willem M. Vos & Hanne L. P. Tytgat, 2024. "Binding of Akkermansia muciniphila to mucin is O-glycan specific," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Bashar Shuoker & Michael J. Pichler & Chunsheng Jin & Hiroka Sakanaka & Haiyang Wu & Ana Martínez Gascueña & Jining Liu & Tine Sofie Nielsen & Jan Holgersson & Eva Nordberg Karlsson & Nathalie Juge & , 2023. "Sialidases and fucosidases of Akkermansia muciniphila are crucial for growth on mucin and nutrient sharing with mucus-associated gut bacteria," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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