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Structural basis for nutrient acquisition by dominant members of the human gut microbiota

DOI: 10.1038/nature20828 DOI Help

Authors: Amy J. Glenwright (Newcastle University) , Karunakar R. Pothula (Jacobs University Bremen) , Satya P. Bhamidimarri (Jacobs University Bremen) , Dror S. Chorev (University of Oxford) , Arnaud Basle (Newcastle University) , Susan J. Firbank (Newcastle University) , Hongjun Zheng (Newcastle University) , Carol V. Robinson (University of Oxford) , Mathias Winterhalter (Jacobs University Bremen) , Ulrich Kleinekathöfer (Jacobs University Bremen) , David N. Bolam (Newcastle University) , Bert Van Den Berg (Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 541 , PAGES 407 - 411

State: Published (Approved)
Published: January 2017
Diamond Proposal Number(s): 9948

Abstract: The human large intestine is populated by a high density of microorganisms, collectively termed the colonic microbiota1, which has an important role in human health and nutrition2. The survival of microbiota members from the dominant Gram-negative phylum Bacteroidetes depends on their ability to degrade dietary glycans that cannot be metabolized by the host3. The genes encoding proteins involved in the degradation of specific glycans are organized into co-regulated polysaccharide utilization loci4, 5, 6, 7, 8, with the archetypal locus sus (for starch utilisation system) encoding seven proteins, SusA–SusG8, 9, 10. Glycan degradation mainly occurs intracellularly and depends on the import of oligosaccharides by an outer membrane protein complex composed of an extracellular SusD-like lipoprotein and an integral membrane SusC-like TonB-dependent transporter4, 5, 6, 7, 11, 12, 13. The presence of the partner SusD-like lipoprotein is the major feature that distinguishes SusC-like proteins from previously characterized TonB-dependent transporters. Many sequenced gut Bacteroides spp. encode over 100 SusCD pairs, of which the majority have unknown functions and substrate specificities3, 8, 14, 15. The mechanism by which extracellular substrate binding by SusD proteins is coupled to outer membrane passage through their cognate SusC transporter is unknown. Here we present X-ray crystal structures of two functionally distinct SusCD complexes purified from Bacteroides thetaiotaomicron and derive a general model for substrate translocation. The SusC transporters form homodimers, with each β-barrel protomer tightly capped by SusD. Ligands are bound at the SusC–SusD interface in a large solvent-excluded cavity. Molecular dynamics simulations and single-channel electrophysiology reveal a ‘pedal bin’ mechanism, in which SusD moves away from SusC in a hinge-like fashion in the absence of ligand to expose the substrate-binding site to the extracellular milieu. These data provide mechanistic insights into outer membrane nutrient import by members of the microbiota, an area of major importance for understanding human–microbiota symbiosis.

Journal Keywords: Bacterial structural biology; Dietary carbohydrates; Membrane biophysics; X-ray crystallography; Microbial communities

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 02/02/2017 13:46

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