title: Allosteric catch bond properties of the FimH adhesin from Salmonella enterica serovar Typhimurium.
abstract: Despite sharing the name and the ability to mediate mannose-sensitive adhesion, the type 1 fimbrial FimH adhesins of Salmonella Typhimurium and Escherichia coli share only 15% sequence identity. In the present study, we demonstrate that even with this limited identity in primary sequence, these two proteins share remarkable similarity of complex receptor binding and structural properties. In silico simulations suggest that, like E. coli FimH, Salmonella FimH has a two-domain tertiary structure topology, with a mannose-binding pocket located on the apex of a lectin domain. Structural analysis of mutations that enhance S. Typhimurium FimH binding to eukaryotic cells and mannose-BSA demonstrated that they are not located proximal to the predicted mannose-binding pocket but rather occur in the vicinity of the predicted interface between the lectin and pilin domains of the adhesin. This implies that the functional effect of such mutations is indirect and probably allosteric in nature. By analogy with E. coli FimH, we suggest that Salmonella FimH functions as an allosteric catch bond adhesin, where shear-induced separation of the lectin and pilin domains results in a shift from a low affinity to a high affinity binding conformation of the lectin domain. Indeed, we observed shear-enhanced binding of whole bacteria expressing S. Typhimurium type 1 fimbriae. In addition, we observed that anti-FimH antibodies activate rather than inhibit S. Typhimurium FimH mannose binding, consistent with the allosteric catch bond properties of this adhesin.
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington 98195.
authors.forename: Dagmara I
authors.initials: DI
authors.lastname: Kisiela
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington 98195.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Kramer
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington 98195.
authors.forename: Veronika
authors.initials: V
authors.lastname: Tchesnokova
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington 98195.
authors.forename: Pavel
authors.initials: P
authors.lastname: Aprikian
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington 98195.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yarov-Yarovoy
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, Iowa 52242.
authors.forename: Steven
authors.initials: S
authors.lastname: Clegg
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington 98195. Electronic address: evs@u.washington.edu.
authors.forename: Evgeni V
authors.initials: EV
authors.lastname: Sokurenko
mesh_terms: D018829:Adhesins, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000495:Allosteric Site; D000595:Amino Acid Sequence; D001422:Bacterial Adhesion; D001426:Bacterial Proteins / Q000378:metabolism; D002241:Carbohydrates / Q000737:chemistry; D008358:Mannose / Q000737:chemistry; D008969:Molecular Sequence Data; D016296:Mutagenesis; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D012486:Salmonella typhimurium / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D018829:Adhesins, Bacterial; D001426:Bacterial Proteins; D002241:Carbohydrates; D008358:Mannose