The binding mechanism of the virulence factor Streptococcus suis adhesin P subtype to globotetraosylceramide is associated with systemic disease release_54ptsycymjhlnlm7mugsun7iry

by Miralda M. Johansson, Eva Bélurier, Anastassios Papageorgiou, Anders P. Sundin, Jani Rahkila, Teemu Kallonen, Ulf J. Nilsson, Santeri Maatsola, Thomas K.M. Nyholm, Jarmo Käpylä, Jukka Corander, Reko Leino (+3 others)

Published in Journal of Biological Chemistry by American Society for Biochemistry & Molecular Biology (ASBMB).

2020   Volume 295, Issue 42, jbc.RA120.014818

Abstract

<jats:italic>Streptococcus suis</jats:italic> is part of the pig commensal microbiome but strains can also be pathogenic, causing pneumonia and meningitis in pigs as well as zoonotic meningitis. According to genomic analysis, <jats:italic>S. suis</jats:italic> is divided into asymptomatic carriage, respiratory and systemic strains with distinct genomic signatures. Since the strategies to target pathogenic <jats:italic>S. suis</jats:italic> are limited, new therapeutic approaches are needed. The virulence factor <jats:italic>S. suis</jats:italic> adhesin P (SadP) recognizes the galabiose Galα1–4Gal-oligosaccharide. Based on its oligosaccharide fine specificity, SadP can be divided into subtypes P<jats:sub>N</jats:sub> and P<jats:sub>O</jats:sub>. We show here that subtype P<jats:sub>N</jats:sub> is distributed in the systemic strains causing meningitis, whereas type P<jats:sub>O</jats:sub> is found in asymptomatic carriage and respiratory strains. Both types of SadP are shown to predominantly bind to pig lung globotriaosylceramide (Gb3). However, SadP adhesin from systemic subtype P<jats:sub>N</jats:sub> strains also binds to globotetraosylceramide (Gb4). Mutagenesis studies of the galabiose-binding domain of type P<jats:sub>N</jats:sub> SadP adhesin showed that the amino acid asparagine-285, which is replaced by an aspartate residue in type P<jats:sub>O</jats:sub> SadP, was required for binding to Gb4 and, strikingly, was also required for interaction with the glycomimetic inhibitor phenylurea-galabiose. Molecular dynamics simulations provided insight into the role of Asn-285 for Gb4 and phenylurea-galabiose binding, suggesting additional hydrogen bonding to terminal GalNAc of Gb4 and urea-group. Thus, the Asn-285-mediated molecular mechanism of type P<jats:sub>N</jats:sub> SadP binding to Gb4 could be used to selectively target <jats:italic>S. suis</jats:italic> in systemic disease without interfering with commensal strains, opening up new avenues for interventional strategies against this pathogen.
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