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

Sci Adv. 2017 Feb 10;3(2):e1601944. doi: 10.1126/sciadv.1601944. eCollection 2017 Feb.


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: Bladder epithelium; Chaperone usher pili; Escherichia coli; FimH; Molecular Tethering; Protein Allostery; Protein Conformation; Urinary tract infection; adhesin; positive selection.

MeSH terms

  • Adhesins, Escherichia coli* / chemistry
  • Adhesins, Escherichia coli* / genetics
  • Adhesins, Escherichia coli* / metabolism
  • Animals
  • Escherichia coli Infections* / genetics
  • Escherichia coli Infections* / metabolism
  • Escherichia coli Infections* / pathology
  • Escherichia coli* / chemistry
  • Escherichia coli* / pathogenicity
  • Escherichia coli* / physiology
  • Female
  • Fimbriae Proteins* / chemistry
  • Fimbriae Proteins* / genetics
  • Fimbriae Proteins* / metabolism
  • Host-Parasite Interactions / physiology*
  • Mice
  • Protein Domains
  • Urinary Bladder* / metabolism
  • Urinary Bladder* / microbiology
  • Urinary Bladder* / physiology
  • Urinary Tract Infections* / genetics
  • Urinary Tract Infections* / metabolism
  • Urinary Tract Infections* / microbiology
  • Urinary Tract Infections* / pathology


  • Adhesins, Escherichia coli
  • fimH protein, E coli
  • Fimbriae Proteins