Research ArticleBIOMOLECULES

Evolutionary fine-tuning of conformational ensembles in FimH during host-pathogen interactions

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Science Advances  10 Feb 2017:
Vol. 3, no. 2, e1601944
DOI: 10.1126/sciadv.1601944

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Abstract

Positive selection in the two-domain type 1 pilus adhesin FimH enhances Escherichia coli fitness in urinary tract infection (UTI). We report a comprehensive atomic-level view of FimH in two-state conformational ensembles in solution, composed of one low-affinity tense (T) and multiple high-affinity relaxed (R) conformations. Positively selected residues allosterically modulate the equilibrium between these two conformational states, each of which engages mannose through distinct binding orientations. A FimH variant that only adopts the R state is severely attenuated early in a mouse model of uncomplicated UTI but is proficient at colonizing catheterized bladders in vivo or bladder transitional-like epithelial cells in vitro. Thus, the bladder habitat has barrier(s) to R state–mediated colonization possibly conferred by the terminally differentiated bladder epithelium and/or decoy receptors in urine. Together, our studies reveal the conformational landscape in solution, binding mechanisms, and adhesive strength of an allosteric two-domain adhesin that evolved “moderate” affinity to optimize persistence in the bladder during UTI.

Keywords
  • Urinary tract infection
  • Escherichia coli
  • FimH
  • adhesin
  • positive selection
  • Chaperone usher pili
  • Bladder epithelium
  • Protein Conformation
  • Protein Allostery
  • Molecular Tethering

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

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