Abstract
The mucosal microbiota is recognised as an important factor for our health, with many disease states linked to imbalances in the normal community structure. Hence, there is considerable interest in identifying the molecular basis of human-microbe interactions. In this work we investigated the capacity of microbes to thrive on mucosal surfaces, either as mutualists, commensals or pathogens, using comparative genomics to identify co-occurring molecular traits. We identified a novel domain we named M60-like/PF13402 (new Pfam entry PF13402), which was detected mainly among proteins from animal host mucosa-associated prokaryotic and eukaryotic microbes ranging from mutualists to pathogens. Lateral gene transfers between distantly related microbes explained their shared M60-like/PF13402 domain. The novel domain is characterised by a zinc-metallopeptidase-like motif and is distantly related to known viral enhancin zinc-metallopeptidases. Signal peptides and/or cell surface anchoring features were detected in most microbial M60-like/PF13402 domain-containing proteins, indicating that these proteins target an extracellular substrate. A significant subset of these putative peptidases was further characterised by the presence of associated domains belonging to carbohydrate-binding module family 5/12, 32 and 51 and other glycan-binding domains, suggesting that these novel proteases are targeted to complex glycoproteins such as mucins. An in vitro mucinase assay demonstrated degradation of mammalian mucins by a recombinant form of an M60-like/PF13402-containing protein from the gut mutualist Bacteroides thetaiotaomicron. This study reveals that M60-like domains are peptidases targeting host glycoproteins. These peptidases likely play an important role in successful colonisation of both vertebrate mucosal surfaces and the invertebrate digestive tract by both mutualistic and pathogenic microbes. Moreover, 141 entries across various peptidase families described in the MEROPS database were also identified with carbohydrate-binding modules defining a new functional context for these glycan-binding domains and providing opportunities to engineer proteases targeting specific glycoproteins for both biomedical and industrial applications.
Highlights
The cells of our resident microbiota are estimated to outnumber human cells by factor of 10 and to encode in toto a significantly more extensive proteomes than the human genome [1]
The most significant hits included proteins from bacteria known to be able to thrive on mammalian mucosal surfaces including, Mycoplasma penetrans a human mucosal pathogen that can infect the urogenital tract (UGT) and respiratory tract (RT) [33] and Clostridium perfringens that can infect the gastrointestinal tract (GIT) of various mammals [34]
Two microbial species living on mammalian mucosa, T. vaginalis and Bacteroides caccae were endowed with the largest hit list with 26 and 16 distinct annotated proteins, respectively
Summary
The cells of our resident microbiota are estimated to outnumber human cells by factor of 10 and to encode in toto a significantly more extensive proteomes than the human genome [1] This vast microbial proteome can be considered as an extension of our own as microorganisms are known to mediate numerous metabolic capabilities not carried out by mammalian cells and influence important aspects of human development, immunity and nutrition [1,2]. There is currently tremendous interest in investigating the proteome complement of the human mucosal microbiota, as the mucosal surfaces are the dominant interface for host-microbe interactions, with microbial cell surface and secreted proteins likely representing key players mediating interactions for both mutualistic and pathogenic outcomes [4,5,6]. These sugar chains are usually O-linked and can make up
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