Co-crystal structure of sterol regulatory element binding protein 1a at 2.3 A resolution

Structure. 1998 May 15;6(5):661-72. doi: 10.1016/s0969-2126(98)00067-7.

Abstract

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.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Basic-Leucine Zipper Transcription Factors
  • Binding Sites
  • CCAAT-Enhancer-Binding Proteins*
  • Calcium / chemistry
  • Cholesterol / metabolism
  • DNA / chemistry*
  • DNA-Binding Proteins / chemistry*
  • Dimerization
  • Fatty Acids / metabolism
  • Gene Expression Regulation
  • Helix-Loop-Helix Motifs*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Proteins / chemistry*
  • Nucleic Acid Conformation
  • Protein Binding
  • Protein Conformation
  • Regulatory Sequences, Nucleic Acid*
  • Sequence Homology, Amino Acid
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors / chemistry*

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Basic-Leucine Zipper Transcription Factors
  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Fatty Acids
  • MAX protein, human
  • Myc associated factor X
  • Nuclear Proteins
  • SREBF1 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • DNA
  • Cholesterol
  • Calcium

Associated data

  • PDB/1AM9