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

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The binding mechanism of the virulence factor Streptococcus suis adhesin P subtype to globotetraosylceramide is associated with systemic disease. / Madar Johansson, Miralda; Bélurier, Eva; Papageorgiou, Anastassios C.; Sundin, Anders P.; Rahkila, Jani; Kallonen, Teemu; Nilsson, Ulf J.; Maatsola, Santeri; Nyholm, Thomas K.M.; Käpylä, Jarmo; Corander, Jukka; Leino, Reko; Finne, Jukka; Teneberg, Susann; Haataja, Sauli.

I: The Journal of biological chemistry, Vol. 295, Nr. 42, 2020, s. 14305-14324.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Madar Johansson, M, Bélurier, E, Papageorgiou, AC, Sundin, AP, Rahkila, J, Kallonen, T, Nilsson, UJ, Maatsola, S, Nyholm, TKM, Käpylä, J, Corander, J, Leino, R, Finne, J, Teneberg, S & Haataja, S 2020, 'The binding mechanism of the virulence factor Streptococcus suis adhesin P subtype to globotetraosylceramide is associated with systemic disease', The Journal of biological chemistry, vol. 295, nr. 42, s. 14305-14324. https://doi.org/10.1074/jbc.RA120.014818

APA

Madar Johansson, M., Bélurier, E., Papageorgiou, A. C., Sundin, A. P., Rahkila, J., Kallonen, T., Nilsson, U. J., Maatsola, S., Nyholm, T. K. M., Käpylä, J., Corander, J., Leino, R., Finne, J., Teneberg, S., & Haataja, S. (2020). The binding mechanism of the virulence factor Streptococcus suis adhesin P subtype to globotetraosylceramide is associated with systemic disease. The Journal of biological chemistry, 295(42), 14305-14324. https://doi.org/10.1074/jbc.RA120.014818

CBE

Madar Johansson M, Bélurier E, Papageorgiou AC, Sundin AP, Rahkila J, Kallonen T, Nilsson UJ, Maatsola S, Nyholm TKM, Käpylä J, Corander J, Leino R, Finne J, Teneberg S, Haataja S. 2020. The binding mechanism of the virulence factor Streptococcus suis adhesin P subtype to globotetraosylceramide is associated with systemic disease. The Journal of biological chemistry. 295(42):14305-14324. https://doi.org/10.1074/jbc.RA120.014818

MLA

Vancouver

Author

Madar Johansson, Miralda ; Bélurier, Eva ; Papageorgiou, Anastassios C. ; Sundin, Anders P. ; Rahkila, Jani ; Kallonen, Teemu ; Nilsson, Ulf J. ; Maatsola, Santeri ; Nyholm, Thomas K.M. ; Käpylä, Jarmo ; Corander, Jukka ; Leino, Reko ; Finne, Jukka ; Teneberg, Susann ; Haataja, Sauli. / The binding mechanism of the virulence factor Streptococcus suis adhesin P subtype to globotetraosylceramide is associated with systemic disease. I: The Journal of biological chemistry. 2020 ; Vol. 295, Nr. 42. s. 14305-14324.

RIS

TY - JOUR

T1 - The binding mechanism of the virulence factor Streptococcus suis adhesin P subtype to globotetraosylceramide is associated with systemic disease

AU - Madar Johansson, Miralda

AU - Bélurier, Eva

AU - Papageorgiou, Anastassios C.

AU - Sundin, Anders P.

AU - Rahkila, Jani

AU - Kallonen, Teemu

AU - Nilsson, Ulf J.

AU - Maatsola, Santeri

AU - Nyholm, Thomas K.M.

AU - Käpylä, Jarmo

AU - Corander, Jukka

AU - Leino, Reko

AU - Finne, Jukka

AU - Teneberg, Susann

AU - Haataja, Sauli

PY - 2020

Y1 - 2020

N2 - Streptococcus suis 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, S. suis is divided into asymptomatic carriage, respiratory and systemic strains with distinct genomic signatures. Because the strategies to target pathogenic S. suis are limited, new therapeutic approaches are needed. The virulence factor S. suis adhesin P (SadP) recognizes the galabiose Galα1-4Gal-oligosaccharide. Based on its oligosaccharide fine specificity, SadP can be divided into subtypes PN and PO We show here that subtype PN is distributed in the systemic strains causing meningitis, whereas type PO 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 PN strains also binds to globotetraosylceramide (Gb4). Mutagenesis studies of the galabiose-binding domain of type PN SadP adhesin showed that the amino acid asparagine 285, which is replaced by an aspartate residue in type PO 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 the urea group. Thus, the Asn-285-mediated molecular mechanism of type PN SadP binding to Gb4 could be used to selectively target S. suis in systemic disease without interfering with commensal strains, opening up new avenues for interventional strategies against this pathogen.

AB - Streptococcus suis 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, S. suis is divided into asymptomatic carriage, respiratory and systemic strains with distinct genomic signatures. Because the strategies to target pathogenic S. suis are limited, new therapeutic approaches are needed. The virulence factor S. suis adhesin P (SadP) recognizes the galabiose Galα1-4Gal-oligosaccharide. Based on its oligosaccharide fine specificity, SadP can be divided into subtypes PN and PO We show here that subtype PN is distributed in the systemic strains causing meningitis, whereas type PO 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 PN strains also binds to globotetraosylceramide (Gb4). Mutagenesis studies of the galabiose-binding domain of type PN SadP adhesin showed that the amino acid asparagine 285, which is replaced by an aspartate residue in type PO 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 the urea group. Thus, the Asn-285-mediated molecular mechanism of type PN SadP binding to Gb4 could be used to selectively target S. suis in systemic disease without interfering with commensal strains, opening up new avenues for interventional strategies against this pathogen.

KW - adhesin

KW - cell surface receptor

KW - Gb3

KW - Gb4

KW - globotetraosylceramide

KW - globotriaosylceramide

KW - glycobiology

KW - glycolipid

KW - ligand-binding protein

KW - SadP

U2 - 10.1074/jbc.RA120.014818

DO - 10.1074/jbc.RA120.014818

M3 - Article

C2 - 32796033

AN - SCOPUS:85093705611

VL - 295

SP - 14305

EP - 14324

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 42

ER -