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Structural basis of lipid biosynthesis regulation in Gram-positive bacteria

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.
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Submitted on : Saturday, April 25, 2020 - 12:08:56 AM
Last modification on : Thursday, May 14, 2020 - 1:27:22 AM

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Gustavo Schujman, Marcelo Guerin, Alejandro Buschiazzo, Francis Schaeffer, Leticia Llarrull, et al.. Structural basis of lipid biosynthesis regulation in Gram-positive bacteria. EMBO Journal, EMBO Press, 2006, 25 (17), pp.4074-4083. ⟨10.1038/sj.emboj.7601284⟩. ⟨pasteur-02554108⟩

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