Abstact

LysR-type transcriptional regulators (LTTRs) are a diverse family of proteins that regulate various cellular processes, including motility in bacteria. In Escherichia coli, the LTTR LrhA represses flagellar biosynthesis by inhibiting the flhDC operon. However, the structural basis underlying this regulation has remained unclear. Here, we determined both a high-resolution crystal structure and a cryo-EM reconstruction of LrhA, revealing a predominant and stable tetrameric organization with pronounced structural variability in its effector-binding region. Structural and biochemical analyses demonstrate that mutations in these variable regions perturb the oligomeric equilibrium of LrhA, shifting the balance between tetrameric and dimeric species. This shift correlates with enhanced DNA binding affinity and stronger repression of the flhDC promoter. While ligand binding may similarly modulate LrhA activity, our data primarily support a model in which alterations in oligomeric state mediated by the variable regions regulate LrhA function. Together, these findings provide a structural framework for understanding how LrhA controls bacterial motility and offer broader insights into oligomerization-based regulation within the LTTR family.