Structural basis for adaptation of lactobacilli to gastrointestinal mucus

<jats:title>Summary</jats:title> <jats:p> The mucus layer covering the gastrointestinal ( <jats:styled-content style="fixed-case">GI</jats:styled-content> ) epithelium is critical in selecting and maintaining homeostatic interactions with our gut bacteria. However, the underpinning mechanisms of these interactions are not understood. Here, we provide structural and functional insights into the canonical mucus‐binding protein ( <jats:styled-content style="fixed-case">MUB</jats:styled-content> ), a multi‐repeat cell‐surface adhesin found in <jats:styled-content style="fixed-case"> <jats:italic>L</jats:italic> </jats:styled-content> <jats:italic>actobacillus</jats:italic> inhabitants of the <jats:styled-content style="fixed-case">GI</jats:styled-content> tract. <jats:styled-content style="fixed-case">X</jats:styled-content> ‐ray crystallography together with small‐angle <jats:styled-content style="fixed-case">X</jats:styled-content> ‐ray scattering demonstrated a ‘beads on a string’ arrangement of repeats, generating 174 nm long protein fibrils, as shown by atomic force microscopy. Each repeat consists of tandemly arranged Ig‐ and mucin‐binding protein ( <jats:styled-content style="fixed-case">MucBP</jats:styled-content> ) modules. The binding of full‐length <jats:styled-content style="fixed-case">MUB</jats:styled-content> was confined to mucus via multiple interactions involving terminal sialylated mucin glycans. While individual <jats:styled-content style="fixed-case">MUB</jats:styled-content> domains showed structural similarity to fimbrial proteins from <jats:styled-content style="fixed-case">G</jats:styled-content> ram‐positive pathogens, the particular organization of <jats:styled-content style="fixed-case">MUB</jats:styled-content> provides a structural explanation for the mechanisms in which lactobacilli have adapted to their host niche by maximizing interactions with the mucus receptors, potentiating the retention of bacteria within the mucus layer. Together, this study reveals functional and structural features which may affect tropism of microbes across mucus and along the <jats:styled-content style="fixed-case">GI</jats:styled-content> tract, providing unique insights into the mechanisms adopted by commensals and probiotics to adapt to the mucosal environment. </jats:p>