Transcription regulating factor CSL-Notch-Mastermind/DNA complex
Caenorhabditis elegans (nematode)
Notch signaling mediates communication between cells and is essential for proper embryonic patterning and development. This signaling is regulated by CSL, a DNA binding transcription factor that regulates transcription of Notch target genes by interacting with coregulators. CSL regulates both repression and activation of Notch target genes. In the absence of a signal, CSL represses the transcription of Notch target genes by recruiting corepressor proteins to form a transcriptional repressor complex which presumably converts the local chromatin into transcriptionally silent form. In the presence of a signal, CSL activates transcription of Notch target genes. Notch signaling occurs when the ligand DSL on the surface of one interacts with the receptor Notch on a neighboring cell. This interaction induces the cleavage of Notch, which results in the release of intracellular portion of Notch (NotchIC) from the membrane. Subsequently, NotchIC localizes to the nucleus and binds to CSL. This NotchIC-CSL interaction induces the conformational change of CSL and results in the dissociation of transcriptional corepressors from CSL. Then a transcriptional coactivator, Mastermind binds to CDL. This CSL-NotchIC-Mastermind ternary complex is the activator of transcription of Notch target genes.
The structure described here is DNA binding CSL-NotchIC-Mastermind complex. CSL contains three domains, N terminal domain (NTD), beta-trefoil domain (BTD), and C terminal domain (CTD). NTD and CTD are structurally homologous, but only NTD interacts with the major groove of DNA and CTD does not contact with DNA. Additionally, BTD interact with the minor groove of DNA. NotchIC contains three domains, RAM domain (RAM), ankyrin repeats (ANK), and PEST sequence. NotchIC interacts with CSL through its RAM and ANK binding to the BTD and CTD of CSL, respectively. Especially, RAM-BTD interaction is thought to contribute to the dissociation of the corepressor from CSL. Mastermind interacts with ANK of NotchIC and NTD and CTD of CSL through its N terminal domain. Formation of CSL-NotchIC-Mastermind ternary complex induces large structural change within the CSL while maintaining similar DNA binding contacts and specificity. This mechanism converts CSL from a repressor to an activator of transcription.
Protein Data Bank (PDB)
author: Daisuke Ino