Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-32021-9
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Funding
- ARAID
- Agencia Estatal de Investigacion (AEI) [BFU2016-75633-P, PID2019-105451GB-I00, RTI2018-099592-B-C21, PID2020-118893GB-I00]
- Fondo Europeo de Desarrollo Regional (FEDER)
- Spanish Structures of Excellence Maria de Maeztu [MDM-2017-0767]
- Gobierno de Aragon [E34_R17, LMP58_18]
- FEDER (2014-2020) funds for Building Europe from Aragon
- Danish National Research Foundation [DNRF107]
- COST Action [CA18103 INNOGLY]
- European Research Council [ERC-2020-SyG-951231]
- Marie Skodowska-Curie Innovative Training Networks [H2020-MSCA-ITN-2018-814102]
- Spanish Ministry of Science, Innovation and Universities
- AGAUR [2019 BP 00129]
- FAPESP [2016/24191-8]
- Mizutani Foundation [210086]
- FP7 (2007-2013) under BioStruct-X [283570, BIOSTRUCTX_5186]
- Mizutani Foundation for Glycoscience [220115]
- EU (Marie-Sklodowska Curie ITN, DIRNANO) [956544]
- Novo Nordisk Foundation
- Lundbeck Foundation
- Marie Curie Actions (MSCA) [956544] Funding Source: Marie Curie Actions (MSCA)
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This study provides molecular insights into the interaction between mucinase AM0627 and O-glycans in gut bacteria. The enzyme specifically cleaves bis-T O-glycopeptides by recognizing both the sugar moieties and the peptide sequence. Structural comparison reveals a conserved residue responsible for the common activity of AM0627 and another mucinase with bis-T/Tn substrates.
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 (Gal beta 1-3GalNAc alpha 1-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 (GalNAc alpha 1-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-pi 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. AM0627 is a bis-O-glycan mucinase that might work in the final steps of mucus degradation, thereby providing a carbon and nitrogen source for Akkermansia muciniphila. Here, the authors provide molecular insights into AM0627 function from X-ray crystallography and computer simulations.
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