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

Vasilios Kalas, Jerome S. Pinkner, Thomas J. Hannan, Michael E. Hibbing, Karen W. Dodson, Alex S. Holehouse, Hao Zhang, Niraj H. Tolia, Michael L. Gross, Rohit V. Pappu, James Janetka, Scott J. Hultgren

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish
Article numbere1601944
JournalScience Advances
Volume3
Issue number2
DOIs
StatePublished - Feb 2017

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