Structural Insights into the Interaction Between CRTCs and 14-3-3

J Mol Biol. 2021 Apr 2;433(7):166874. doi: 10.1016/j.jmb.2021.166874. Epub 2021 Feb 5.

Abstract

The CREB-Regulated Transcriptional Coactivators (CRTCs) regulate the transcription of CREB target genes and have important functions in many biological processes. At the basal state, they are phosphorylated at multiple residues, which promotes their association with 14-3-3 that sequesters them in the cytoplasm. Upon dephosphorylation, they translocate into the nuclei and associate with CREB to activate the target gene transcription. Although three conserved serine residues in CRTCs have been implicated in their phosphorylation regulation, whether and how they mediate interactions with 14-3-3 is unclear. Here, we provide direct evidence that these residues and flanking regions interact with 14-3-3 and the structural basis of the interaction. Our study also identified a novel salt bridge in CRTC1 with an important function in binding 14-3-3, expanding the understanding of the interaction between 14-3-3 and its ligands.

Keywords: CREB; X-ray crystallography; phosphorylation; protein–protein interaction; transcription activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / genetics*
  • CREB-Binding Protein / genetics*
  • Cell Nucleus / genetics
  • Cyclic AMP Response Element-Binding Protein / genetics*
  • Cytoplasm / genetics
  • HEK293 Cells
  • Humans
  • Phosphorylation / genetics
  • Protein Binding / genetics
  • Transcription Factors / genetics*
  • Transcription, Genetic / genetics
  • Transcriptional Activation / genetics

Substances

  • 14-3-3 Proteins
  • CREB1 protein, human
  • CRTC1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Transcription Factors
  • CREB-Binding Protein