Conformational Motion in Gene Regulatory Proteins

Proteins' structures determine functions and the functions determine the structures. Yet, proteins and other biological macromolecules are dynamic systems under continuous conformational motion and the motions are keys to many of the biological processes in which they are involved. We argue that conformational motion driven by structural specificities, and not structures alone, determines biological functions. For instance conformational motion in gene regulatory proteins acts as a selective molecular switch motion in DNA binding mode and controls gene regulations. Perhaps, such action is relatively well studied in prokaryotic OxyR belonging to LysR family of transcriptional regulatory proteins. Escherichia coli Oxidative stress response genes are transcriptionally regulated by OxyR through a reversibly reducible cysteine disulfide biosensor. The redox status in these cysteines induces structural changes which are conformationally transmitted to the dimer subunit interfaces and alters DNA binding mode. However, crystal structures of Porphyromonas gingivalis OxyR regulatory domains indicate locked dimer configuration insensitive to cysteine disulfide redox status and shows only one activating mode. Conformational motion in Porphyromonas gingivalis OxyR changes dimer/tetramer convention (dimer binding to DNA or tetramer binding to DNA) and alters differentiation in gene regulations. Crystal structures along with modeled full-length Porphyromonas gingivalis, Escherichia coli and Neisseria meningitidis OxyR-DNA complexes predict different DNA binding modes in these organisms and indicate how the limited conformational motion differentiates the species. Aerobic organisms' OxyR is confined in open dimer configuration; Anaerobe's OxyR is confined in closed dimer form, while facultative organisms can conformationally switch OxyR dimer configurations. Conformational motion in aerobes and anaerobes OxyR is restricted by dimer configuration and can only change dimer/tetramer population while in facultative organisms conformational motion induces configurational switch in dimers.