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

Stéphane Mouilleron¹, Carola A. Langer^2*, Sebastian Guettler^2*, Neil Q. McDonald^1,3, and Richard Treisman²

¹ Structural Biology Group, Cancer Research UK London Research Institute, Lincoln’s Inn Fields Laboratories, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK.
² Transcription Group, Cancer Research UK London Research Institute, Lincoln’s Inn Fields Laboratories, London WC2A 3LY, UK.
³ Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, Malet Street, London WC1E 7HX, UK.

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

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.

To whom correspondence should be addressed. E-mail: Neil.McDonald{at}cancer.org.uk (N.Q.M.); Richard.Treisman{at}cancer.org.uk (R.T.)

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