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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, Harris, Gemma, Speakman, Adrian, Jones, Richard P O, Leech, Andrew, Turkenburg, Johan P and Potts, Jennifer R (2011) Structural and functional analysis of the tandem β-zipper interaction of a streptococcal protein with human fibronectin. The Journal of biological chemistry, 286 (44). pp. 38311-38320. ISSN 1083-351X

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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.

      Item Type: Article
      Subjects: Q Science > Q Science (General)
      Schools: School of Applied Sciences
      School of Applied Sciences > Biomolecular Sciences Research Centre
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      Depositing User: Richard Bingham
      Date Deposited: 13 Oct 2011 13:22
      Last Modified: 17 Jan 2012 12:24
      URI: http://eprints.hud.ac.uk/id/eprint/11644

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