High force catch bond mechanism of bacterial adhesion in the human gut

• Published in: Nature communications Vol. 11; no. 1; p. 4321
• Main Authors: Liu, Zhaowei, Liu, Haipei, Vera, Andrés M., Bernardi, Rafael C., Tinnefeld, Philip, Nash, Michael A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.08.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 119/118; 147/3; 631/326/41/2536; 639/638/45/303; 639/925/350/1056; Adhesion; Adhesive strength; Bacteria; Bacterial Adhesion - genetics; Bacterial Adhesion - physiology; Binding; Cell adhesion; Cell adhesion & migration; Cell Cycle Proteins; Cellulose; Cellulose fibers; Chromosomal Proteins, Non-Histone; Cohesin; Cohesins; Colonization; Computer simulation; Digestive system; Digestive tract; Experimental methods; Fibers; Fluorescence resonance energy transfer; Gastrointestinal Microbiome - physiology; Gastrointestinal Tract - microbiology; Gene Knockout Techniques; Humanities and Social Sciences; Humans; Intestinal microflora; Intestine; Kinetics; Loading rate; Mechanical Phenomena; Mechanical properties; Molecular dynamics; Molecular Dynamics Simulation; Molecular modelling; Monte Carlo Method; multidisciplinary; Physical Phenomena; Protein Binding; Protein Conformation; Science; Science (multidisciplinary); Shear forces; Shear stress; Simulation; Single Molecule Imaging; Spectroscopy; Stress, Mechanical; Substrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18063-x

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 ~500 pN and the other at ~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. Understanding bacterial adhesion is important in a number of different areas of study. Here using a range of simulations and experimental methods, the authors, report on the molecular mechanism behind the binding of bacteria to cellulose fibers at high shear force in the human gut.