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Liu, Zhaowei, Liu, Haipei, Vera, Andres M., Bernardi, Rafael C., Tinnefeld, Philip ORCID logoORCID: https://orcid.org/0000-0003-4290-7770 and Nash, Michael A. (2020): High force catch bond mechanism of bacterial adhesion in the human gut. In: Nature Communications, Vol. 11, No. 1, 4321 [PDF, 1MB]


Bacterial colonization of the human intestine requires firm adhesion of bacteria to insoluble substrates under hydrodynamic flow. Here we report the molecular mechanism behind an ultrastable protein complex responsible for resisting shear forces and adhering bacteria to cellulose fibers in the human gut. Using single-molecule force spectroscopy (SMFS), single-molecule FRET (smFRET), and molecular dynamics (MD) simulations, we resolve two binding modes and three unbinding reaction pathways of a mechanically ultrastable R. champanellensis (Rc) Dockerin:Cohesin (Doc:Coh) complex. The complex assembles in two discrete binding modes with significantly different mechanical properties, with one breaking at similar to 500 pN and the other at similar to 200 pN at loading rates from 1-100 nN s(-1). A neighboring X-module domain allosterically regulates the binding interaction and inhibits one of the low-force pathways at high loading rates, giving rise to a catch bonding mechanism that manifests under force ramp protocols. Multi-state Monte Carlo simulations show strong agreement with experimental results, validating the proposed kinetic scheme. These results explain mechanistically how gut microbes regulate cell adhesion strength at high shear stress through intricate molecular mechanisms including dual-binding modes, mechanical allostery and catch bonds.

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