Structural basis for the transcriptional regulation of membrane lipid homeostasis.
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.
Miller
Darcie J
DJ
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Zhang
Yong-Mei
YM
Subramanian
Chitra
C
Rock
Charles O
CO
White
Stephen W
SW
D000214:Acyl Coenzyme A / Q000737:chemistry / Q000378:metabolism; D000494:Allosteric Regulation; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics*; D008563:Membrane Lipids / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011550:Pseudomonas aeruginosa / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
D000214:Acyl Coenzyme A; D001426:Bacterial Proteins; D005227:Fatty Acids; D008563:Membrane Lipids; D050505:Mutant Proteins; D004247:DNA