Seminar

Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Gram-positive bacteria

Marcelo Guerin, PhD

"FapR is a transcription factor that negatively controls the expression of several genes of the fatty acid and phospholipid biosynthesis in Bacillus subtilis and Staphylococus aureus. It is the first global regulator of lipid synthesis discovered in bacteria and is largely conserved in Gram positive organisms. A key intermediate in fatty acid biosynthesis, malonyl-CoA, acts as a negative effector of the transcriptional repressor FapR. The crystal structure of FapR reveals a homodimeric protein with a thioesterase-like 'hot-dog' fold effector domain. Binding of malonyl-CoA promotes a disorder-to-order transition, which transforms an open ligand-binding groove into a long tunnel occupied by the effector molecule in the complex. This ligand-induced modification propagates to the helix-turn-helix motifs, impairing their productive association for DNA binding. Structure-based mutations that disrupt the FapR-malonyl-CoA interaction prevent DNA-binding regulation and result in a lethal phenotype in B. subtilis and S. aureus, suggesting this homeostatic signaling pathway as a promising target for novel chemotherapeutic agents against Gram-positive pathogens."