As stated earlier, DesT senses the composition of lipid rather than only the concentration of a ligand. The ability to differentially respond to alternate ligand shapes allows it to function as a 'rheostat' in membrane lipid homeostasis. Helix α6 within the binding domain, specifically residues Phe71, Phe96, Phe166 and L169 sense which ligand is bound and alter the hydrophobic core to create specifically shaped cavities to accommodate the ligand's structure. The movement of α6 results in coordination of helices α4 and α5.
As helices α4 and α6 are shared in both DNA and ligand binding domains, their movements in response to the shape of the bound ligand affect the relative positioning of the paired DNA-binding domain.
In the tense state, the dimeric structure is stabilized by the tighter association of the paired α6 helices, which involves multiple interactions centered on Tyr115, and the formation of the L8-L9 interfacial clamp. The protomer can be considered as being destabilized by a partial unwinding and bending of helix α4 caused by the rotation of the Phe71 side chain. The opposite is true in the relaxed state, where the α6 helices only marginally interact and α4 is not distorted.
The UFA:SFA ratio in phospholipids is a key determinant of membrane biophysical properties, and the ability of DesT to monitor this ratio and appropriately moderate gene expression to direct cellular fatty acid metabolism is a brilliant mechanism that ensures the phospholipid biosynthetic pathway will be supplied with a balanced fatty acid composition. A key feature of this mechanism is that it allows DesT to appropriately adjust gene expression even when the intracellular concentration of acyl-CoA is saturating the transcription factor.
The DesT structural paradigm may apply to other regulators of lipid metabolism where metabolic end products and intermediates are abundant and the biophysical properties of the mixture are more important to control than the concentration of a specific molecule.
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