Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes

Nat Struct Mol Biol. 2010 Nov;17(11):1312-7. doi: 10.1038/nsmb.1938. Epub 2010 Oct 24.

Abstract

Ligand-induced proteolysis of Notch produces an intracellular effector domain that transduces essential signals by regulating the transcription of target genes. This function relies on the formation of transcriptional activation complexes that include intracellular Notch, a Mastermind co-activator and the transcription factor CSL bound to cognate DNA. These complexes form higher-order assemblies on paired, head-to-head CSL recognition sites. Here we report the X-ray structure of a dimeric human Notch1 transcription complex loaded on the paired site from the human HES1 promoter. The small interface between the Notch ankyrin domains could accommodate DNA bending and untwisting to allow a range of spacer lengths between the two sites. Cooperative dimerization occurred on the human and mouse Hes5 promoters at a sequence that diverged from the CSL-binding consensus at one of the sites. These studies reveal how promoter organizational features control cooperativity and, thus, the responsiveness of different promoters to Notch signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / chemistry
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Binding Sites
  • Conserved Sequence
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism
  • Dimerization
  • Homeodomain Proteins / chemistry
  • Homeodomain Proteins / metabolism
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / chemistry
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Promoter Regions, Genetic*
  • Protein Structure, Tertiary
  • Receptor, Notch1 / chemistry*
  • Receptor, Notch1 / metabolism
  • Repressor Proteins / chemistry
  • Transcription Factor HES-1
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • MAML1 protein, human
  • NOTCH1 protein, human
  • RBPJ protein, human
  • Receptor, Notch1
  • Repressor Proteins
  • Transcription Factor HES-1
  • Transcription Factors
  • HES5 protein, human
  • HES1 protein, human

Associated data

  • PDB/3NBN