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Title: A Structural Model for Binding of the Serine-Rich Repeat Adhesin GspB to Host Carbohydrate Receptors

Abstract

GspB is a serine-rich repeat (SRR) adhesin of Streptococcus gordonii that mediates binding of this organism to human platelets via its interaction with sialyl-T antigen on the receptor GPIb{alpha}. This interaction appears to be a major virulence determinant in the pathogenesis of infective endocarditis. To address the mechanism by which GspB recognizes its carbohydrate ligand, we determined the high-resolution x-ray crystal structure of the GspB binding region (GspB{sub BR}), both alone and in complex with a disaccharide precursor to sialyl-T antigen. Analysis of the GspB{sub BR} structure revealed that it is comprised of three independently folded subdomains or modules: (1) an Ig-fold resembling a CnaA domain from prokaryotic pathogens; (2) a second Ig-fold resembling the binding region of mammalian Siglecs; (3) a subdomain of unique fold. The disaccharide was found to bind in a pocket within the Siglec subdomain, but at a site distinct from that observed in mammalian Siglecs. Confirming the biological relevance of this binding pocket, we produced three isogenic variants of S. gordonii, each containing a single point mutation of a residue lining this binding pocket. These variants have reduced binding to carbohydrates of GPIb{alpha}. Further examination of purified GspB{sub BR}-R484E showed reduced binding to sialyl-T antigenmore » while S. gordonii harboring this mutation did not efficiently bind platelets and showed a significant reduction in virulence, as measured by an animal model of endocarditis. Analysis of other SRR proteins revealed that the predicted binding regions of these adhesins also had a modular organization, with those known to bind carbohydrate receptors having modules homologous to the Siglec and Unique subdomains of GspBBR. This suggests that the binding specificity of the SRR family of adhesins is determined by the type and organization of discrete modules within the binding domains, which may affect the tropism of organisms for different tissues.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ;  [1]
  1. VA
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
AHAUNIVERSITYNIH
OSTI Identifier:
1031944
Resource Type:
Journal Article
Journal Name:
PLoS Patho.
Additional Journal Information:
Journal Volume: 7; Journal Issue: (7) ; 07, 2011
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ANIMALS; ANTIGENS; CARBOHYDRATES; CRYSTAL STRUCTURE; DISACCHARIDES; GENE MUTATIONS; LINERS; MUTATIONS; PATHOGENESIS; PATHOGENS; PRECURSOR; PROTEINS; RESIDUES; SPECIFICITY; STREPTOCOCCUS; STRUCTURAL MODELS; VIRULENCE

Citation Formats

Pyburn, Tasia M., Bensing, Barbara A., Xiong, Yan Q., Melancon, Bruce J., Tomasiak, Thomas M., Ward, Nicholas J., Yankovskaya, Victoria, Oliver, Kevin M., Cecchini, Gary, Sulikowski, Gary A., Tyska, Matthew J., Sullam, Paul M., Iverson, T. M., UCLA), Vanderbilt), and UCSF). A Structural Model for Binding of the Serine-Rich Repeat Adhesin GspB to Host Carbohydrate Receptors. United States: N. p., 2014. Web. doi:10.1371/journal.ppat.1002112.
Pyburn, Tasia M., Bensing, Barbara A., Xiong, Yan Q., Melancon, Bruce J., Tomasiak, Thomas M., Ward, Nicholas J., Yankovskaya, Victoria, Oliver, Kevin M., Cecchini, Gary, Sulikowski, Gary A., Tyska, Matthew J., Sullam, Paul M., Iverson, T. M., UCLA), Vanderbilt), & UCSF). A Structural Model for Binding of the Serine-Rich Repeat Adhesin GspB to Host Carbohydrate Receptors. United States. https://doi.org/10.1371/journal.ppat.1002112
Pyburn, Tasia M., Bensing, Barbara A., Xiong, Yan Q., Melancon, Bruce J., Tomasiak, Thomas M., Ward, Nicholas J., Yankovskaya, Victoria, Oliver, Kevin M., Cecchini, Gary, Sulikowski, Gary A., Tyska, Matthew J., Sullam, Paul M., Iverson, T. M., UCLA), Vanderbilt), and UCSF). 2014. "A Structural Model for Binding of the Serine-Rich Repeat Adhesin GspB to Host Carbohydrate Receptors". United States. https://doi.org/10.1371/journal.ppat.1002112.
@article{osti_1031944,
title = {A Structural Model for Binding of the Serine-Rich Repeat Adhesin GspB to Host Carbohydrate Receptors},
author = {Pyburn, Tasia M. and Bensing, Barbara A. and Xiong, Yan Q. and Melancon, Bruce J. and Tomasiak, Thomas M. and Ward, Nicholas J. and Yankovskaya, Victoria and Oliver, Kevin M. and Cecchini, Gary and Sulikowski, Gary A. and Tyska, Matthew J. and Sullam, Paul M. and Iverson, T. M. and UCLA) and Vanderbilt) and UCSF)},
abstractNote = {GspB is a serine-rich repeat (SRR) adhesin of Streptococcus gordonii that mediates binding of this organism to human platelets via its interaction with sialyl-T antigen on the receptor GPIb{alpha}. This interaction appears to be a major virulence determinant in the pathogenesis of infective endocarditis. To address the mechanism by which GspB recognizes its carbohydrate ligand, we determined the high-resolution x-ray crystal structure of the GspB binding region (GspB{sub BR}), both alone and in complex with a disaccharide precursor to sialyl-T antigen. Analysis of the GspB{sub BR} structure revealed that it is comprised of three independently folded subdomains or modules: (1) an Ig-fold resembling a CnaA domain from prokaryotic pathogens; (2) a second Ig-fold resembling the binding region of mammalian Siglecs; (3) a subdomain of unique fold. The disaccharide was found to bind in a pocket within the Siglec subdomain, but at a site distinct from that observed in mammalian Siglecs. Confirming the biological relevance of this binding pocket, we produced three isogenic variants of S. gordonii, each containing a single point mutation of a residue lining this binding pocket. These variants have reduced binding to carbohydrates of GPIb{alpha}. Further examination of purified GspB{sub BR}-R484E showed reduced binding to sialyl-T antigen while S. gordonii harboring this mutation did not efficiently bind platelets and showed a significant reduction in virulence, as measured by an animal model of endocarditis. Analysis of other SRR proteins revealed that the predicted binding regions of these adhesins also had a modular organization, with those known to bind carbohydrate receptors having modules homologous to the Siglec and Unique subdomains of GspBBR. This suggests that the binding specificity of the SRR family of adhesins is determined by the type and organization of discrete modules within the binding domains, which may affect the tropism of organisms for different tissues.},
doi = {10.1371/journal.ppat.1002112},
url = {https://www.osti.gov/biblio/1031944}, journal = {PLoS Patho.},
number = (7) ; 07, 2011,
volume = 7,
place = {United States},
year = {Thu Oct 02 00:00:00 EDT 2014},
month = {Thu Oct 02 00:00:00 EDT 2014}
}