Structural basis of lipid biosynthesis regulation in Gram-positive bacteria

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Abstract
Malonyl‐CoA is an essential intermediate in fatty acid synthesis in all living cells. Here we demonstrate a new role for this molecule as a global regulator of lipid homeostasis in Gram‐positive bacteria. Using in vitro transcription and binding studies, we demonstrate that malonyl‐CoA is a direct and specific inducer of Bacillus subtilis FapR, a conserved transcriptional repressor that regulates the expression of several genes involved in bacterial fatty acid and phospholipid synthesis. The crystal structure of the effector‐binding domain of FapR reveals a homodimeric protein with a thioesterase‐like ‘hot‐dog’ fold. 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, suggesting this homeostatic signaling pathway as a promising target for novel chemotherapeutic agents against Gram‐positive pathogens.