Review Article Classification, Structural Biology, And Applications Of Mucin Domain-Targeting Proteases

The human gastrointestinal tract harbors an astonishing number of microbial species, collectively called the gut microbiota, which play an incredibly important role in human health and disease [1-4]. Together, the commensal bacteria stimulate gut cell maturation and proliferation, foster proper immune development, and protect host cells against pathogenic species [5]. To survive in the harsh environment of the gut, most bacteria use dietary fibers and starches as a nutrient source, but a subset of these species can also digest and metabolize host glycans and glycoproteins [6]. In particular, mucins are a class of proteins characterized by a variable number of tandem repeatsEpithelial surfaces throughout the body are coated by mucins, a class of proteins carrying domains characterized by a high density of O-glycosylated serine and threonine residues. The resulting mucosal layers form crucial host-microbe interfaces that prevent the translocation of microbes while also selecting for distinct bacteria via the presented glycan repertoire. The intricate interplay between mucus production and breakdown thus determines the composition of the microbiota maintained within these mucosal environments, which can have a large influence on the host during both homeostasis and disease. Most research to date on mucus breakdown has focused on glycosidases that trim glycan structures to release monosaccharides as a source of nutrients. More recent work has uncovered the existence of mucin-type O-glycosylation-dependent proteases that are secreted by pathogens, commensals, and mutualists to facilitate mucosal colonization and penetration. Additionally, immunoglobulin A (IgA) proteases promote bacterial colonization in the presence of neutralizing secretory IgA through selective cleavage of the heavily O-glycosylated hinge region. In this review, we summarize families of O-glycoproteases and IgA proteases, discuss known structural features, and review applications of these enzymes to glycobiology.