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  • The EMBO Journal (2008) 27, 3198 - 3208
  • doi:10.1038/emboj.2008.235

Published online: 13 November 2008

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

Stephane Mouilleron1,a, Sebastian Guettler2,ab, Carola A Langer2, Richard Treisman2 and Neil Q McDonald1,3

  1. Structural Biology Laboratory, Cancer Research UK, London Research Institute, London, UK
  2. Transcription Laboratory, Cancer Research UK, London Research Institute, London, UK
  3. School of Crystallography, Birkbeck College, London, UK

Correspondence to:

Richard Treisman, Transcription Laboratories, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. Tel.: +44 207 269 3727; Fax: +44 207 269 3093; E-mail: richard.treisman@cancer.org.uk

Neil Q McDonald, Structural Biology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. Tel.: +44 207 269 3259; Fax: +44 207 269 3258; E-mail: neil.mcdonald@cancer.org.uk

aThese authors contributed equally to this work

bPresent address: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Canada M5G 1X5

Received 6 August 2008; Accepted 10 October 2008

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 RPELMAL peptide:G-actin complexes. Both RPEL peptides bind to the G-actin hydrophobic cleft and to subdomain 3. These RPELMAL:G-actin structures explain the sequence conservation defining the RPEL motif, including the invariant arginine. Characterisation of the RPELMAL: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 RPELMAL structures. Comparison with other actin-binding proteins reveals an unexpected similarity to the vitamin-D-binding protein, extending the G-actin-binding protein repertoire.

  • Keywords:

    • actin,
    • MAL,
    • RPEL,
    • SRF,
    • structure

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