title: Structural basis of tropism of Escherichia coli to the bladder during urinary tract infection.
abstract: The first step in the colonization of the human urinary tract by pathogenic Escherichia coli is the mannose-sensitive binding of FimH, the adhesin present at the tip of type 1 pili, to the bladder epithelium. We elucidated crystallographically the interactions of FimH with D-mannose. The unique site binding pocket occupied by D-mannose was probed using site-directed mutagenesis. All but one of the mutants examined had greatly diminished mannose-binding activity and had also lost the ability to bind human bladder cells. The binding activity of the mono-saccharide D-mannose was delineated from this of mannotriose (Man(alpha 1-3)[Man(alpha 1-6)]Man) by generating mutants that abolished D-mannose binding but retained mannotriose binding activity. Our structure/function analysis demonstrated that the binding of the monosaccharide alpha-D-mannose is the primary bladder cell receptor for uropathogenic E. coli and that this event requires a highly conserved FimH binding pocket. The residues in the FimH mannose-binding pocket were sequenced and found to be invariant in over 200 uropathogenic strains of E. coli. Only enterohaemorrhagic E. coli (EHEC) possess a sequence variation within the mannose-binding pocket of FimH, suggesting a naturally occurring mechanism of attenuation in EHEC bacteria that would prevent them from being targeted to the urinary tract.
authors: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Chia-Suei
authors: CS
authors: Hung
authors: Julie
authors: J
authors: Bouckaert
authors: Danielle
authors: D
authors: Hung
authors: Jerome
authors: J
authors: Pinkner
authors: Charlotte
authors: C
authors: Widberg
authors: Anthony
authors: A
authors: DeFusco
authors: C Gale
authors: CG
authors: Auguste
authors: Robert
authors: R
authors: Strouse
authors: Solomon
authors: S
authors: Langermann
authors: Gabriel
authors: G
authors: Waksman
authors: Scott J
authors: SJ
authors: Hultgren
mesh_terms: D018829:Adhesins, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018830:Adhesins, Escherichia coli; D000595:Amino Acid Sequence; D001422:Bacterial Adhesion; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004797:Enzyme-Linked Immunosorbent Assay; D004848:Epithelium / Q000382:microbiology; D004926:Escherichia coli / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D029968:Escherichia coli Proteins; D036781:Fimbriae Proteins; D010861:Fimbriae, Bacterial / Q000235:genetics / Q000502:physiology; D006801:Humans; D008358:Mannose / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D016415:Sequence Alignment; D001743:Urinary Bladder / Q000382:microbiology*; D014552:Urinary Tract Infections / Q000382:microbiology*
chemical_list: D018829:Adhesins, Bacterial; D018830:Adhesins, Escherichia coli; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; C489721:fimC protein, E coli; C058769:fimH protein, E coli; D036781:Fimbriae Proteins; D008358:Mannose