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Evolutionary fine‐tuning of conformational ensembles in FimH during host‐pathogen interactions
Author(s) -
Kalas Vasilios,
Pinkner Jerome S.,
Hannan Thomas J.,
Hibbing Michael E.,
Janetka James W.,
Hultgren Scott J.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.761.14
Subject(s) - bacterial adhesin , pilus , allosteric regulation , escherichia coli , chemistry , pathogen , adhesion , fimbria , biophysics , host (biology) , microbiology and biotechnology , biology , receptor , biochemistry , genetics , gene , organic chemistry
Positive selection in the two‐domain type 1 pilus adhesin FimH enhances Escherichia coli fitness in urinary tract infection (UTI). Here, 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 engage 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 proficient at colonizing bladder transitional‐like epithelial cells in vitro or catheterized bladders. Thus, the bladder habitat possesses 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.