Structural and functional analysis of the tandem β-zipper interaction of a streptococcal protein with human fibronectin

Nicole C. Norris, Richard J. Bingham, Gemma Harris, Adrian Speakman, Richard P O Jones, Andrew P. Leech, Johan P. Turkenburg, Jennifer R. Potts

Research output: Contribution to journalArticle

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Abstract

Bacterial fibronectin-binding proteins (FnBPs) contain a large intrinsically disordered region (IDR) that mediates adhesion of bacteria to host tissues, and invasion of host cells, through binding to fibronectin (Fn). These FnBP IDRs consist of Fn-binding repeats (FnBRs) that form a highly extended tandem β-zipper interaction on binding to the N-terminal domain of Fn. Several FnBR residues are highly conserved across bacterial species, and here we investigate their contribution to the interaction. Mutation of these residues to alanine in SfbI-5 (a disordered FnBR from the human pathogen Streptococcus pyogenes) reduced binding, but for each residue the change in free energy of binding was <2 kcal/mol. The structure of an SfbI-5 peptide in complex with the second and third F1 modules from Fn confirms that the conserved FnBR residues play equivalent functional roles across bacterial species. Thus, in SfbI-5, the binding energy for the tandem β-zipper interaction with Fn is distributed across the interface rather than concentrated in a small number of "hot spot" residues that are frequently observed in the interactions of folded proteins. We propose that this might be a common feature of the interactions of IDRs and is likely to pose a challenge for the development of small molecule inhibitors of FnBP-mediated adhesion to and invasion of host cells.

Original languageEnglish
Pages (from-to)38311-38320
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number44
DOIs
Publication statusPublished - 4 Nov 2011

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Functional analysis
Fasteners
Fibronectins
Structural analysis
Proteins
Carrier Proteins
Adhesion
Streptococcus pyogenes
Pathogens
Binding energy
Alanine
Free energy
Bacteria
Tissue
Peptides
Mutation
Molecules

Cite this

Norris, Nicole C. ; Bingham, Richard J. ; Harris, Gemma ; Speakman, Adrian ; Jones, Richard P O ; Leech, Andrew P. ; Turkenburg, Johan P. ; Potts, Jennifer R. / Structural and functional analysis of the tandem β-zipper interaction of a streptococcal protein with human fibronectin. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 44. pp. 38311-38320.
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Structural and functional analysis of the tandem β-zipper interaction of a streptococcal protein with human fibronectin. / Norris, Nicole C.; Bingham, Richard J.; Harris, Gemma; Speakman, Adrian; Jones, Richard P O; Leech, Andrew P.; Turkenburg, Johan P.; Potts, Jennifer R.

In: Journal of Biological Chemistry, Vol. 286, No. 44, 04.11.2011, p. 38311-38320.

Research output: Contribution to journalArticle

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