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The binding mechanism of Streptococcus suis accessory virulence factor and adhesin SadP to globotetraosylceramide

By Miralda Madar Johansson, Eva Bélurier, Anastassios C. Papageorgiou, Anders P. Sundin, Jani Rahkila, Teemu Kallonen, Ulf J. Nilsson, Santeri Maatsola, Thomas K.M. Nyholm, Jarmo Käpylä, Jukka Corander, Reko Leino, Jukka Finne, Susann Teneberg, Sauli Haataja

Posted 29 May 2020
bioRxiv DOI: 10.1101/2020.05.29.122762

Streptococcus suis is part of the pig commensal microbiome and a major pig pathogen causing pneumonia and meningitis, occasionally also in humans. The genomic analysis divides S. suis to asymptomatic carriage, respiratory and invasive systemic strains with distinct genomic signatures. The virulence factor S. suis adhesin P (SadP) recognizes the galabiose Galα1−4Gal-oligosaccharide. Based on the oligosaccharide fine specificity, SadP can be divided into subtypes PN and PO. We show that subtype PN is distributed in the systemic strains. Both types of SadP are shown to predominantly bind to pig lung globotriaosylceramide (Gb3). SadP adhesin from virulent subtype PN strain also binds to globotetraosylceramide (Gb4). Mutants of type PN SadP adhesin were constructed into the galabiose-binding domain and analyzed to reveal the mechanism for Gb4 binding. Functional and structural analysis of type PN SadP mutants showed that amino acid N285 of the galabiose-binding site was required for binding to Gb4 and strikingly was also required for interaction with the glycomimetic inhibitor phenylurea-galabiose. Molecular dynamics simulations provided further insight into the role of N285 for Gb4 and phenylurea-galabiose binding, suggesting additional hydrogen bonding to terminal GalNAc of Gb4 and urea-group. Importantly, type PN SadP adhesin expressed by strains causing invasive systemic disease binds via a distinct amino acid N285 mediated mechanism to Gb4. Thus, this molecular mechanism of type PN SadP binding is a candidate for selectively targeting S. suis meningitis without interfering with commensal strains, which opens up new venues for developing intervention strategies against this pathogen. ### Competing Interest Statement The authors have declared no competing interest.

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