Molecular basis for G-actin binding to RPEL motifs from the serum response factor coactivator MAL

EMBO J. 2008 Dec 3;27(23):3198-208. doi: 10.1038/emboj.2008.235. Epub 2008 Nov 13.


Serum response factor transcriptional activity is controlled through interactions with regulatory cofactors such as the coactivator MAL/MRTF-A (myocardin-related transcription factor A). MAL is itself regulated in vivo by changes in cellular actin dynamics, which alter its interaction with G-actin. The G-actin-sensing mechanism of MAL/MRTF-A resides in its N-terminal domain, which consists of three tandem RPEL repeats. We describe the first molecular insights into RPEL function obtained from structures of two independent RPEL(MAL) peptide:G-actin complexes. Both RPEL peptides bind to the G-actin hydrophobic cleft and to subdomain 3. These RPEL(MAL):G-actin structures explain the sequence conservation defining the RPEL motif, including the invariant arginine. Characterisation of the RPEL(MAL):G-actin interaction by fluorescence anisotropy and cell reporter-based assays validates the significance of actin-binding residues for proper MAL localisation and regulation in vivo. We identify important differences in G-actin engagement between the two RPEL(MAL) structures. Comparison with other actin-binding proteins reveals an unexpected similarity to the vitamin-D-binding protein, extending the G-actin-binding protein repertoire.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / chemistry*
  • Actins / metabolism*
  • Amino Acid Sequence
  • Binding Sites
  • Circular Dichroism
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism*
  • Fluorescence Polarization
  • Genes, Reporter
  • Luciferases / genetics
  • Luciferases / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Oncogene Proteins, Fusion / chemistry*
  • Oncogene Proteins, Fusion / metabolism*
  • Protein Binding
  • Protein Structure, Quaternary*
  • Sequence Alignment
  • Trans-Activators


  • Actins
  • DNA-Binding Proteins
  • MRTFA protein, human
  • Oncogene Proteins, Fusion
  • Trans-Activators
  • Luciferases