Structural basis for the role of serine-rich repeat proteins from <i>Lactobacillus reuteri</i> in gut microbe–host interactions

Abstract

<i>Lactobacillus reuteri</i>, a Gram-positive bacterial species inhabiting the gastrointestinal tract of vertebrates, displays remarkable host adaptation. Previous mutational analyses of rodent strain <i>L. reuteri</i> 100-23C identified a gene encoding a predicted surface-exposed serine-rich repeat protein (SRRP_100-23) that was vital for <i>L. reuteri</i> biofilm formation in mice. SRRPs have emerged as an important group of surface proteins on many pathogens, but no structural information is available in commensal bacteria. Here we report the 2.00-Å and 1.92-Å crystal structures of the binding regions (BRs) of SRRP_100-23 and SRRP₅₃₆₀₈ from <i>L. reuteri</i> ATCC 53608, revealing a unique β-solenoid fold in this important adhesin family. SRRP₅₃₆₀₈-BR bound to host epithelial cells and DNA at neutral pH and recognized polygalacturonic acid (PGA), rhamnogalacturonan I, or chondroitin sulfate A at acidic pH. Mutagenesis confirmed the role of the BR putative binding site in the interaction of SRRP₅₃₆₀₈-BR with PGA. Long molecular dynamics simulations showed that SRRP₅₃₆₀₈-BR undergoes a pH-dependent conformational change. Together, these findings provide mechanistic insights into the role of SRRPs in host-microbe interactions and open avenues of research into the use of biofilm-forming probiotics against clinically important pathogens.