Phosphorylation of CREB at Ser-133 induces complex formation with CREB-binding protein via a direct mechanism

Mol Cell Biol. 1996 Feb;16(2):694-703. doi: 10.1128/MCB.16.2.694.


We have characterized a phosphoserine binding domain in the coactivator CREB-binding protein (CBP) which interacts with the protein kinase A-phosphorylated, and hence activated, form of the cyclic AMP-responsive factor CREB. The CREB binding domain, referred to as KIX, is alpha helical and binds to an unstructured kinase-inducible domain in CREB following phosphorylation of CREB at Ser-133. Phospho-Ser-133 forms direct contacts with residues in KIX, and these contacts are further stabilized by hydrophobic residues in the kinase-inducible domain which flank phospho-Ser-133. Like the src homology 2 (SH2) domains which bind phosphotyrosine-containing peptides, phosphoserine 133 appears to coordinate with a single arginine residue (Arg-600) in KIX which is conserved in the CBP-related protein P300. Since mutagenesis of Arg-600 to Gln severely reduces CREB-CBP complex formation, our results demonstrate that, as in the case of tyrosine kinase pathways, signal transduction through serine/threonine kinase pathways may also require protein interaction motifs which are capable of recognizing phosphorylated amino acids.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Binding, Competitive
  • CREB-Binding Protein
  • Circular Dichroism
  • Cross-Linking Reagents
  • Cyclic AMP / pharmacology
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Mice
  • Models, Biological
  • Molecular Sequence Data
  • Mutagenesis
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Serine / metabolism
  • Trans-Activators*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic


  • Cross-Linking Reagents
  • Cyclic AMP Response Element-Binding Protein
  • Nuclear Proteins
  • Peptide Fragments
  • Trans-Activators
  • Transcription Factors
  • Serine
  • Cyclic AMP
  • CREB-Binding Protein
  • Crebbp protein, mouse
  • Cyclic AMP-Dependent Protein Kinases