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Structure of a Pentavalent G-Actin*MRTF-A Complex Reveals How G-Actin Controls Nucleocytoplasmic Shuttling of a Transcriptional Coactivator

DOI: 10.1126/scisignal.2001750 DOI Help
PMID: 21673315 PMID Help

Authors: Stephane Mouilleron (Cancer Research UK) , Carola Langer (Cancer Research UK) , Sebastian Guettler (Cancer Research UK) , Neil McDonald (Cancer Research UK) , Richard Treisman (Cancer Research UK)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science Signaling , VOL 4 (177) , PAGES ra40 - ra40

State: Published (Approved)
Published: June 2011
Diamond Proposal Number(s): 6385

Abstract: Subcellular localization of the actin-binding transcriptional coactivator MRTF-A is controlled by its interaction with monomeric actin (G-actin). Signal-induced decreases in G-actin concentration reduce MRTF-A nuclear export, leading to its nuclear accumulation, whereas artificial increases in G-actin concentration in resting cells block MRTF-A nuclear import, retaining it in the cytoplasm. This regulation is dependent on three actin-binding RPEL motifs in the regulatory domain of MRTF-A. We describe the structures of pentavalent and trivalent G-actin•RPEL domain complexes. In the pentavalent complex, each RPEL motif and the two intervening spacer sequences bound an actin monomer, forming a compact assembly. In contrast, the trivalent complex lacked the C-terminal spacer- and RPEL-actins, both of which bound only weakly in the pentavalent complex. Cytoplasmic localization of MRTF-A in unstimulated fibroblasts also required binding of G-actin to the spacer sequences. The bipartite MRTF-A nuclear localization sequence was buried in the pentameric assembly, explaining how increases in G-actin concentration prevent nuclear import of MRTF-A. Analyses of the pentavalent and trivalent complexes show how actin loads onto the RPEL domain and reveal a molecular mechanism by which actin can control the activity of one of its binding partners.

Journal Keywords: Active; Cell; Amino; Animals ; Cell; Fibroblasts ; Mice ; Multiprotein; NIH; Protein; Quaternary ; Protein; Tertiary ; Structure-Activity; Trans-Activators

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography