A previously uncharacterized O-glycopeptidase from Akkermansia muciniphila requires the Tn-antigen for cleavage of the peptide bond

Medley, Brendon J.; Leclaire, Leif; Thompson, Nicole; Mahoney, Keira E.; Pluvinage, B.; Parson, Matthew AH; Burke, John E.; Malaker, Stacy A.; Wakarchuk, Warren W.; Boraston, A.B.

doi:10.1016/j.jbc.2022.102439

Cited by 11 publications

(10 citation statements)

References 46 publications

(62 reference statements)

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“…The observed mainly cell-attached localization of fucosidase and detection of both cell-attached and secreted sialidase activities indicates that sialic acid and fucose removal occurs extracellularly, which is crucial for further mucin glycan breakdown by A. muciniphila exo-glycosidases and endo-glycanases 34 . Strikingly, four of the recently described O -glycopeptidases from A. muciniphila , revealed a preference for either the T- or the Tn-epitopes, whereas the presence of a sialyl decoration abolished or severely impaired their activity 38 – 41 . These findings suggest that a key role of the sialidases is to create sites for A. muciniphila O -glycopeptidases to allow cleavage of the mucin backbone (Fig.…”

Section: Discussionmentioning

confidence: 95%

Sialidases and fucosidases of Akkermansia muciniphila are crucial for growth on mucin and nutrient sharing with mucus-associated gut bacteria

et al. 2023

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The mucolytic human gut microbiota specialist Akkermansia muciniphila is proposed to boost mucin-secretion by the host, thereby being a key player in mucus turnover. Mucin glycan utilization requires the removal of protective caps, notably fucose and sialic acid, but the enzymatic details of this process remain largely unknown. Here, we describe the specificities of ten A. muciniphila glycoside hydrolases, which collectively remove all known sialyl and fucosyl mucin caps including those on double-sulfated epitopes. Structural analyses revealed an unprecedented fucosidase modular arrangement and explained the sialyl T-antigen specificity of a sialidase of a previously unknown family. Cell-attached sialidases and fucosidases displayed mucin-binding and their inhibition abolished growth of A. muciniphila on mucin. Remarkably, neither the sialic acid nor fucose contributed to A. muciniphila growth, but instead promoted butyrate production by co-cultured Clostridia. This study brings unprecedented mechanistic insight into the initiation of mucin O-glycan degradation by A. muciniphila and nutrient sharing between mucus-associated bacteria.

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Section: Discussionmentioning

confidence: 95%

Sialidases and fucosidases of Akkermansia muciniphila are crucial for growth on mucin and nutrient sharing with mucus-associated gut bacteria

et al. 2023

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“…Multidomain mucinases are hypothesized to arrange their noncatalytic domains into an architecture that enables specific recognition of secondary sites along the linear bottle-brush of mucins, 50,55 and recombinant StcE lacking one of these noncatalytic domains showed reduced activity on mucin substrates. 56,57 Interestingly, the related metalloprotease MMP-1 (collagenase) required an accessory domain to bind and cleave the linear triple helix of collagen; 58 structural and functional studies revealed the importance of cooperativity between this enzyme’s catalytic and accessory domains as well as specific interactions between each domain and the collagen triple helix.…”

Section: Resultsmentioning

confidence: 99%

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

Chongsaritsinsuk

Steigmeyer

Mahoney

et al. 2023

Preprint

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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 checkpoint inhibitors in cancer. However, their dense O-glycosylation remains enigmatic both in terms of glycoproteomic landscape and structural dynamics, primarily due to the challenges associated with studying mucin domains. Here, we present a mucinase (SmE) and demonstrate its ability to selectively cleave along the mucin glycoprotein backbone, similar to others of its kind. Unlike other mucinases, though, SmE harbors the unique ability to cleave at residues bearing extremely complex glycans which enabled improved mass spectrometric analysis of several mucins, including the entire TIM family. With this information in-hand, we performed molecular dynamics (MD) simulations of TIM-3 and -4 to demonstrate how glycosylation affects structural features of these proteins. Overall, we present a powerful workflow to better understand the detailed molecular structures of the mucinome.

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“…Some members of the human gut microbiota express endo-acting O -glycanases to initiate mucin degradation ( Crouch et al 2020 ). Another enzyme participating in mucin degradation, O -glycopeptidase, was identified in Akkermansia muciniphila and extensively characterised ( Trastoy et al 2020 ; Medley et al 2022 ). This enzyme possesses a metzincin metalloprotease catalytic motif but the active site specifically recognises a N -acetylgalactosamine (GalNAc) residue α-linked to a serine or threonine residue.…”

Section: Host-microbe Interface At Mucosal Surfacesmentioning

confidence: 99%

The role of the glycome in symbiotic host-microbe interactions

Aminov,

Aminova

2023

Glycobiology

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Glycosylation plays a crucial role in many aspects of cell biology, including cellular and organismal integrity, structure-and-function of many glycosylated molecules in the cell, signal transduction, development, cancer, and in a number of diseases. Besides, at the inter-organismal level of interaction, a variety of glycosylated molecules are involved in the host-microbiota recognition and initiation of downstream signalling cascades depending on the outcomes of the glycome-mediated ascertainment. The role of glycosylation in host-microbe interactions is better elaborated within the context of virulence and pathogenicity in bacterial infection processes but the symbiotic host-microbe relationships also involve substantive glycome-mediated interactions. The works in the latter field have been reviewed to a much lesser extent, and the main aim of this mini-review is to compensate for this deficiency and summarise the role of glycomics in host-microbe symbiotic interactions.

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A previously uncharacterized O-glycopeptidase from Akkermansia muciniphila requires the Tn-antigen for cleavage of the peptide bond

Cited by 11 publications

References 46 publications

Sialidases and fucosidases of Akkermansia muciniphila are crucial for growth on mucin and nutrient sharing with mucus-associated gut bacteria

Sialidases and fucosidases of Akkermansia muciniphila are crucial for growth on mucin and nutrient sharing with mucus-associated gut bacteria

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

The role of the glycome in symbiotic host-microbe interactions

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