Structural basis for the transcriptional regulation of membrane lipid homeostasis

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Abstract
DesT is a bacterial transcription factor that regulates targets which are in turn involved in controlling the unsaturated:saturated fatty acid ratio available for membrane lipid biosynthesis. The structures of DesT bound to various fatty acids now indicates the conformational changes involved in altering DNA binding site affinity, providing a structural basis for responding to changes in the ratio of unsaturated:saturated fatty acids. DesT is a transcriptional repressor that regulates the genes that control the unsaturated:saturated fatty acid ratio available for membrane lipid synthesis. DesT bound to unsaturated acyl-CoA has a high affinity for its cognate palindromic DNA-binding site, whereas DesT bound to saturated acyl-CoA does not bind this site. Structural analyses of the DesT–oleoyl-CoA–DNA and DesT–palmitoyl-CoA complexes reveal that acyl chain shape directly influences the packing of hydrophobic core residues within the DesT ligand-binding domain. These changes are propagated to the paired DNA-binding domains via conformational changes to modulate DNA binding. These structural interpretations are supported by the in vitro and in vivo characterization of site-directed mutants. The regulation of DesT by the unsaturated:saturated ratio of acyl chains rather than the concentration of a single ligand is a paradigm for understanding transcriptional regulation of membrane lipid homeostasis.

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