Catch-bond mechanism of the bacterial adhesin FimH

Sauer, M.M.; Jakob, R.P.; Eras, Jonathan; Baday, Sefer; Eriş, Deniz; Navarra, Giulio; Bernèche, Simon; Ernst, Beat; Maier, Timm; Glockshuber, Rudi

doi:10.1038/ncomms10738

Cited by 190 publications

(288 citation statements)

References 68 publications

Supporting

Mentioning

255

Contrasting

Unclassified

Order By: Relevance

“…Understanding dynamics at atomic level of detail makes it possible to link the experimentally observed intermediate states to the elasticity of the β sheet and to how conformational changes are propagated. During the preparation of this manuscript, a crystal structure was published containing four FimH molecules in the asymmetric unit, three of which locked in an intermediate state with mannose bound to the high affinity conformation of the pocket while the inter‐domain region was in the low affinity conformation and docked to the pilin domain (PDB code 4XOB) 41. This is consistent with the mechanism proposed here that the interconversion between the low and the high affinity state consists of a series of intermediate steps.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of allosteric propagation across a β‐sheet structure investigated by molecular dynamics simulations

Interlandi

Thomas

2016

Proteins

View full text Add to dashboard Cite

The bacterial adhesin FimH consists of an allosterically regulated mannose‐binding lectin domain and a covalently linked inhibitory pilin domain. Under normal conditions, the two domains are bound to each other, and FimH interacts weakly with mannose. However, under tensile force, the domains separate and the lectin domain undergoes conformational changes that strengthen its bond with mannose. Comparison of the crystallographic structures of the low and the high affinity state of the lectin domain reveals conformational changes mainly in the regulatory inter‐domain region, the mannose binding site and a large β sheet that connects the two distally located regions. Here, molecular dynamics simulations investigated how conformational changes are propagated within and between different regions of the lectin domain. It was found that the inter‐domain region moves towards the high affinity conformation as it becomes more compact and buries exposed hydrophobic surface after separation of the pilin domain. The mannose binding site was more rigid in the high affinity state, which prevented water penetration into the pocket. The large central β sheet demonstrated a soft spring‐like twisting. Its twisting motion was moderately correlated to fluctuations in both the regulatory and the binding region, whereas a weak correlation was seen in a direct comparison of these two distal sites. The results suggest a so called “population shift” model whereby binding of the lectin domain to either the pilin domain or mannose locks the β sheet in a rather twisted or flat conformation, stabilizing the low or the high affinity state, respectively. Proteins 2016; 84:990–1008. © 2016 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.

show abstract

Section: Discussionmentioning

confidence: 99%

Mechanism of allosteric propagation across a β‐sheet structure investigated by molecular dynamics simulations

Interlandi

Thomas

2016

Proteins

View full text Add to dashboard Cite

show abstract

“…Therefore, the receptor specificity of the type 1 and P pilus lectin domains may contribute to the observed tropism towards the bladder and/or the kidney during the course of an infection, respectively 40 . FimH can transition from a low-affinity to a high-affinity binding state depending on the tensile forces applied to the pilus 36,[41][42][43][44] .…”

Section: Structure Of the Tip Fibrillummentioning

confidence: 99%

A comprehensive guide to pilus biogenesis in Gram-negative bacteria

2017

View full text Add to dashboard Cite

Pili are critical virulence factors of many Gram-negative pathogens. These surface structures provide bacteria with a link to their outside environments, allowing bacteria to interact with their hosts, other surfaces or with each other. They can even provide a conduit for the exchange of information. The surface chemistries and other biophysical properties of pili are uniquely adapted to the environmental challenges faced by bacteria. The assembly of these surface structures presents a molecular engineering challenge, which bacteria have solved in a variety of unique ways. In this review, we examine recent advances in our structural understanding of various Gram-negative pilus systems and discuss their functional implications.

show abstract

“…These findings suggested the possibility that pFn promoted untethered interactions by a catchbond mechanism. Catch bonds are bonds that become longer lived (dissociate more slowly) as bond force increases, and they are important for strengthening Fn-integrin interactions under tension and stabilizing selectin-mediated leukocyte rolling on PCVs under shear stress (4,13,14,16,17,(37)(38)(39)(40), as well as BBK32-dependent B. burgdorferi-endothelial interactions under vascular shear-stress conditions (7). BBK32-dependent catch bonds are activated at a slightly higher bond force (∼0.25 pN) than the force threshold at which tether elongation occurs (7) (0.1-0.2 pN; Fig.…”

Section: Pfn Promotes Tethering Interactions By Increasing Bond Formamentioning

confidence: 99%

Plasma fibronectin stabilizes Borrelia burgdorferi –endothelial interactions under vascular shear stress by a catch-bond mechanism

Niddam

Ebady

Bansal

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Bacterial dissemination via the cardiovascular system is the most common cause of infection mortality. A key step in dissemination is bacterial interaction with endothelia lining blood vessels, which is physically challenging because of the shear stress generated by blood flow. Association of host cells such as leukocytes and platelets with endothelia under vascular shear stress requires mechanically specialized interaction mechanisms, including force-strengthened catch bonds. However, the biomechanical mechanisms supporting vascular interactions of most bacterial pathogens are undefined. Fibronectin (Fn), a ubiquitous host molecule targeted by many pathogens, promotes vascular interactions of the Lyme disease spirochete Borrelia burgdorferi. Here, we investigated how B. burgdorferi exploits Fn to interact with endothelia under physiological shear stress, using recently developed live cell imaging and particle-tracking methods for studying bacterial-endothelial interaction biomechanics. We found that B. burgdorferi does not primarily target insoluble matrix Fn deposited on endothelial surfaces but, instead, recruits and induces polymerization of soluble plasma Fn (pFn), an abundant protein in blood plasma that is normally soluble and nonadhesive. Under physiological shear stress, caps of polymerized pFn at bacterial poles formed part of mechanically loaded adhesion complexes, and pFn strengthened and stabilized interactions by a catch-bond mechanism. These results show that B. burgdorferi can transform a ubiquitous but normally nonadhesive blood constituent to increase the efficiency, strength, and stability of bacterial interactions with vascular surfaces. Similar mechanisms may promote dissemination of other Fn-binding pathogens.catch bond | fibronectin | force | vascular | bacteria

show abstract

Catch-bond mechanism of the bacterial adhesin FimH

Cited by 190 publications

References 68 publications

Mechanism of allosteric propagation across a β‐sheet structure investigated by molecular dynamics simulations

Mechanism of allosteric propagation across a β‐sheet structure investigated by molecular dynamics simulations

A comprehensive guide to pilus biogenesis in Gram-negative bacteria

Plasma fibronectin stabilizes Borrelia burgdorferi –endothelial interactions under vascular shear stress by a catch-bond mechanism

Contact Info

Product

Resources

About