More complicated than it looks: assembly of Notch pathway transcription complexes

Oncogene. 2008 Sep 1;27(38):5099-109. doi: 10.1038/onc.2008.223.

Abstract

The Notch pathway is a short-range signaling mechanism between neighboring cells that results in changes in gene expression. Extracellular interactions between Notch receptors and ligands trigger proteolytic cleavage of the receptor Notch. Following cleavage, the freed intracellular domain of Notch (NotchIC) moves from the cytoplasm to the nucleus, engaging the DNA-binding transcription factor CBF-1, Su(H), Lag-1 (CSL)--the nuclear effector of the pathway. NotchIC, together with the transcriptional coactivator Mastermind, form a ternary complex with CSL that activates transcription from genes that are responsive to Notch signaling. Illuminating the molecular details that underlie formation of the transcriptionally active CSL-NotchIC-Mastermind ternary complex is key for understanding how genes are turned on in response to a Notch signal. Recently, several studies using biophysical and computational methods have scrutinized how the CSL-NotchIC-Mastermind ternary complex forms and the role individual domains play in this process. These detailed analyses have provided a wealth of molecular insights into the assembly of a Notch pathway active transcription complex but have also raised several intriguing, yet confounding questions. This review will focus on the findings of these recent biophysical studies and provide speculative models that address these unanswered questions.

Publication types

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

MeSH terms

  • Animals
  • Ankyrins / physiology
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / physiology
  • Circular Dichroism
  • Crystallography, X-Ray
  • DNA / metabolism
  • DNA-Binding Proteins / physiology
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / physiology
  • Models, Biological
  • Models, Molecular
  • Multiprotein Complexes
  • Protein Folding
  • Protein Interaction Domains and Motifs
  • Protein Interaction Mapping
  • Receptors, Notch / chemistry
  • Receptors, Notch / physiology*
  • Species Specificity
  • Trans-Activators / physiology
  • Transcription Factors
  • Transcription, Genetic / physiology*

Substances

  • Ankyrins
  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • MAML1 protein, human
  • Multiprotein Complexes
  • Receptors, Notch
  • Trans-Activators
  • Transcription Factors
  • DNA