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

Mouilleron, S; Guettler, S; Langer, CA; Treisman, R; McDonald, NQ; (2008) Molecular basis for G-actin binding to RPEL motifs from the serum response factor coactivator MAL. EMBO J , 27 (23) 3198 - 3208. 10.1038/emboj.2008.235.

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Abstract

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.

Type:Article
Title:Molecular basis for G-actin binding to RPEL motifs from the serum response factor coactivator MAL.
Location:England
DOI:10.1038/emboj.2008.235
Language:English
Additional information:PMCID: PMC2583105
Keywords:Actins, Amino Acid Sequence, Binding Sites, Circular Dichroism, Crystallography, X-Ray, DNA-Binding Proteins, Fluorescence Polarization, Genes, Reporter, Luciferases, Models, Molecular, Molecular Sequence Data, Oncogene Proteins, Fusion, Protein Binding, Protein Structure, Quaternary, Sequence Alignment
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Life Sciences

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