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

Víctor Taleb, Qinghua Liao, Yoshiki Narimatsu, Ana García-García, Ismael Compañón, Rafael Junqueira Borges, Andrés Manuel González-Ramírez, Francisco Corzana, Henrik Clausen, Carme Rovira () and Ramon Hurtado-Guerrero ()
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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
Ramon Hurtado-Guerrero: University of Zaragoza

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32021-9

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