The structural basis of acyl coenzyme A-dependent regulation of the transcription factor FadR.
FadR is an acyl-CoA-responsive transcription factor, regulating fatty acid biosynthetic and degradation genes in Escherichia coli. The apo-protein binds DNA as a homodimer, an interaction that is disrupted by binding of acyl-COA: The recently described structure of apo-FadR shows a DNA binding domain coupled to an acyl-CoA binding domain with a novel fold, but does not explain how binding of the acyl-CoA effector molecule > 30 A away from the DNA binding site affects transcriptional regulation. Here, we describe the structures of the FadR-operator and FadR- myristoyl-CoA binary complexes. The FadR-DNA complex reveals a novel winged helix-turn-helix protein-DNA interaction, involving sequence-specific contacts from the wing to the minor groove. Binding of acyl-CoA results in dramatic conformational changes throughout the protein, with backbone shifts up to 4.5 A. The net effect is a rearrangement of the DNA binding domains in the dimer, resulting in a change of 7.2 A in separation of the DNA recognition helices and the loss of DNA binding, revealing the molecular basis of acyl-CoA-responsive regulation.
van Aalten
D M
DM
Wellcome Trust Biocentre, Division of Biological Chemistry and Molecular Microbiology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK. dava@davapc1.bioch.dundee.ac.uk
DiRusso
C C
CC
Knudsen
J
J
D000214:Acyl Coenzyme A / Q000737:chemistry* / Q000378:metabolism; D000494:Allosteric Regulation; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics
D000214:Acyl Coenzyme A; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C057119:FadR protein, Bacteria; D012097:Repressor Proteins; C040349:S-tetradecanoyl-coenzyme A; D004247:DNA