Structural basis of mammalian mucin processing by the human gut O-glycopeptidase OgpA from Akkermansia muciniphila

Beatriz Trastoy,Andreas Naegeli,Marcelo E Guerin,Itxaso Anso,Jonathan Sjögren

doi:10.1038/s41467-020-18696-y

Abstract

Akkermansia muciniphila is a mucin-degrading bacterium commonly found in the human gut that promotes a beneficial effect on health, likely based on the regulation of mucus thickness and gut barrier integrity, but also on the modulation of the immune system. In this work, we focus in OgpA from A. muciniphila, an O-glycopeptidase that exclusively hydrolyzes the peptide bond N-terminal to serine or threonine residues substituted with an O-glycan. We determine the high-resolution X-ray crystal structures of the unliganded form of OgpA, the complex with the glycodrosocin O-glycopeptide substrate and its product, providing a comprehensive set of snapshots of the enzyme along the catalytic cycle. In combination with O-glycopeptide chemistry, enzyme kinetics, and computational methods we unveil the molecular mechanism of O-glycan recognition and specificity for OgpA. The data also contribute to understanding how A. muciniphila processes mucins in the gut, as well as analysis of post-translational O-glycosylation events in proteins.

Highlights

Akkermansia muciniphila is a mucin-degrading bacterium commonly found in the human gut that promotes a beneficial effect on health, likely based on the regulation of mucus thickness and gut barrier integrity, and on the modulation of the immune system
The gut microbiota maintains a mutualistic relationship with the host: it provides bacteria with access to food, while bacteria contribute to the digestion of complex foods and the synthesis of essential metabolites to the host
The BT4244 and ZmpB enzymes belong to the M60 family, while StcE and IMPa belong to the M66 and M88 families, respectively

Summary

Introduction

Akkermansia muciniphila is a mucin-degrading bacterium commonly found in the human gut that promotes a beneficial effect on health, likely based on the regulation of mucus thickness and gut barrier integrity, and on the modulation of the immune system. Sus-like systems represent up to onefifth of the B. thetaiotaomicron genome, and are widespread among Bacteroidetes members[26,27,28] They participate in the recognition and specificity for a broad range of plant and animal tissue glycans that are expected to enter the human gut, as well as the breakdown of N- and O-linked glycans[21,23,29,30,31,32,33,34,35,36]. A. muciniphila is a mucin-degrading bacterium that promotes a beneficial impact on human health This positive effect has been correlated with the regulation of mucus thickness and gut barrier integrity, and with the modulation of the immune system by interaction with Toll-like receptor 243,44. Such information, as well as the precise mechanisms that A. muciniphila uses to process mucins in the gut, generating a positive impact on health, still remains a challenge

Methods

Results

Conclusion