Structural basis for the transcriptional regulation of membrane lipid homeostasis

Nat Struct Mol Biol. 2010 Aug;17(8):971-5. doi: 10.1038/nsmb.1847. Epub 2010 Jul 18.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acyl Coenzyme A / chemistry
  • Acyl Coenzyme A / metabolism
  • Allosteric Regulation
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Crystallography, X-Ray
  • DNA / chemistry
  • DNA / metabolism
  • Fatty Acids / chemistry
  • Fatty Acids / metabolism
  • Gene Expression Regulation*
  • Homeostasis / genetics*
  • Membrane Lipids / chemistry*
  • Membrane Lipids / genetics
  • Membrane Lipids / metabolism*
  • Models, Molecular
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Protein Binding
  • Protein Structure, Secondary
  • Pseudomonas aeruginosa / metabolism
  • Structure-Activity Relationship
  • Transcription, Genetic*

Substances

  • Acyl Coenzyme A
  • Bacterial Proteins
  • Fatty Acids
  • Membrane Lipids
  • Mutant Proteins
  • DNA

Associated data

  • PDB/3LSJ
  • PDB/3LSP
  • PDB/3LSR