Co-crystal structure of sterol regulatory element binding protein 1a at 2.3 A resolution.
BACKGROUND
The sterol regulatory element binding proteins (SREBPs) are helix-loop-helix transcriptional activators that control expression of genes encoding proteins essential for cholesterol biosynthesis/uptake and fatty acid biosynthesis. Unlike helix-loop-helix proteins that recognize symmetric E-boxes (5'-CANNTG-3'), the SREBPs have a tyrosine instead of a conserved arginine in their basic regions. This difference allows recognition of an asymmetric sterol regulatory element (StRE, 5'-ATCACCCAC-3').


RESULTS
The 2.3 A resolution co-crystal structure of the DNA-binding portion of SREBP-1a bound to an StRE reveals a quasi-symmetric homodimer with an asymmetric DNA-protein interface. One monomer binds the E-box half site of the StRE (5'-ATCAC-3') using sidechain-base contacts typical of other helix-loop-helix proteins. The non-E-box half site (5'-GTGGG-3') is recognized through entirely different protein-DNA contacts.


CONCLUSIONS
Although the SREBPs are structurally similar to the E-box-binding helix-loop-helix proteins, the Arg-->Tyr substitution yields dramatically different DNA-binding properties that explain how they recognize StREs and regulate expression of genes important for membrane biosynthesis.
Párraga
A
A
Laboratories of Molecular Biophysics, Rockefeller University, New York, NY 10021, USA.
Bellsolell
L
L
Ferré-D'Amaré
A R
AR
Burley
S K
SK
D000595:Amino Acid Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins; D002118:Calcium / Q000737:chemistry; D002784:Cholesterol / Q000378:metabolism; D004247:DNA / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000737:chemistry*; D019281:Dimerization; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry*; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D011487:Protein Conformation; D012045:Regulatory Sequences, Nucleic Acid; D017386:Sequence Homology, Amino Acid; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000737:chemistry*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; C499330:MAX protein, human; C067850:Myc associated factor X; D009687:Nuclear Proteins; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D004247:DNA; D002784:Cholesterol; D002118:Calcium