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Uropathogenic E. coli adhesin-induced host cell receptor conformational changes: implications in transmembrane signaling transduction.

ABSTRACT: Urinary tract infection is the second most common infectious disease and is caused predominantly by type 1-fimbriated uropathogenic Escherichia coli (UPEC). UPEC initiates infection by attaching to uroplakin (UP) Ia, its urothelial surface receptor, via the FimH adhesins capping the distal end of its fimbriae. UP Ia, together with UP Ib, UP II, and UP IIIa, forms a 16-nm receptor complex that is assembled into hexagonally packed, two-dimensional crystals (urothelial plaques) covering >90% of the urothelial apical surface. Recent studies indicate that FimH is the invasin of UPEC as its attachment to the urothelial surface can induce cellular signaling events including calcium elevation and the phosphorylation of the UP IIIa cytoplasmic tail, leading to cytoskeletal rearrangements and bacterial invasion. However, it remains unknown how the binding of FimH to the UP receptor triggers a signal that can be transmitted through the highly impermeable urothelial apical membrane. We show here by cryo-electron microscopy that FimH binding to the extracellular domain of UP Ia induces global conformational changes in the entire UP receptor complex, including a coordinated movement of the tightly bundled transmembrane helices. This movement of the transmembrane helix bundles can cause a corresponding lateral translocation of the UP cytoplasmic tails, which can be sufficient to trigger downstream signaling events. Our results suggest a novel pathogen-induced transmembrane signal transduction mechanism that plays a key role in the initial stages of UPEC invasion and receptor-mediated bacterial invasion in general.

SUBMITTER: Wang H

PROVIDER: S-EPMC2755582 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Uropathogenic E. coli adhesin-induced host cell receptor conformational changes: implications in transmembrane signaling transduction.

Wang Huaibin H Min Guangwei G Glockshuber Rudi R Sun Tung-Tien TT Kong Xiang-Peng XP

Journal of molecular biology 20090703 2

Urinary tract infection is the second most common infectious disease and is caused predominantly by type 1-fimbriated uropathogenic Escherichia coli (UPEC). UPEC initiates infection by attaching to uroplakin (UP) Ia, its urothelial surface receptor, via the FimH adhesins capping the distal end of its fimbriae. UP Ia, together with UP Ib, UP II, and UP IIIa, forms a 16-nm receptor complex that is assembled into hexagonally packed, two-dimensional crystals (urothelial plaques) covering >90% of the ...[more]

PMID: 19577575

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Project description:Tsr, the serine chemoreceptor in Escherichia coli, transduces signals from a periplasmic ligand-binding site to its cytoplasmic tip, where it controls the activity of the CheA kinase. To function, Tsr forms trimers of homodimers (TODs), which associate in vivo with the CheA kinase and CheW coupling protein. Together, these proteins assemble into extended hexagonal arrays. Here, we use cryo-electron tomography and molecular dynamics simulation to study Tsr in the context of a near-native array, characterizing its signaling-related conformational changes at both the individual dimer and the trimer level. In particular, we show that individual Tsr dimers within a trimer exhibit asymmetric flexibilities that are a function of the signaling state, highlighting the effect of their different protein interactions at the receptor tips. We further reveal that the dimer compactness of the Tsr trimer changes between signaling states, transitioning at the glycine hinge from a compact conformation in the kinase-OFF state to an expanded conformation in the kinase-ON state. Hence, our results support a crucial role for the glycine hinge: to allow the receptor flexibility necessary to achieve different signaling states while also maintaining structural constraints imposed by the membrane and extended array architecture.IMPORTANCE In Escherichia coli, membrane-bound chemoreceptors, the histidine kinase CheA, and coupling protein CheW form highly ordered chemosensory arrays. In core signaling complexes, chemoreceptor trimers of dimers undergo conformational changes, induced by ligand binding and sensory adaptation, which regulate kinase activation. Here, we characterize by cryo-electron tomography the kinase-ON and kinase-OFF conformations of the E. coli serine receptor in its native array context. We found distinctive structural differences between the members of a receptor trimer, which contact different partners in the signaling unit, and structural differences between the ON and OFF signaling complexes. Our results provide new insights into the signaling mechanism of chemoreceptor arrays and suggest an important functional role for a previously postulated flexible region and glycine hinge in the receptor molecule.

Dataset Information

Uropathogenic E. coli adhesin-induced host cell receptor conformational changes: implications in transmembrane signaling transduction.

Publications

Uropathogenic E. coli adhesin-induced host cell receptor conformational changes: implications in transmembrane signaling transduction.

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