期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 44, 页码 38311-38320出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.276592
关键词
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资金
- British Heart Foundation
- Overseas Research Students Awards Scheme Scholarship
- University of Sydney
- University of York
- Biotechnology and Biological Sciences Research Council [D010608/1]
- Biotechnology and Biological Sciences Research Council [1023651, BB/D010608/1] Funding Source: researchfish
- British Heart Foundation [PG/09/079/28008, FS/07/034/22969] Funding Source: researchfish
- BBSRC [BB/D010608/1] Funding Source: UKRI
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 beta-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 beta-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.
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