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

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

Author information

1
Center for Women's Infectious Disease Research, Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Center for Women's Infectious Disease Research, Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Center for Women's Infectious Disease Research, Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
4
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.
5
Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA.
6
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.

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:

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

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