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Structural basis for MOF and MSL3 recruitment into the dosage compensation complex by MSL1

Nature Structural & Molecular Biology volume 18, pages 142–149 (2011)Cite this article

Abstract

The male-specific lethal (MSL) complex is required for dosage compensation in Drosophila melanogaster, and analogous complexes exist in mammals. We report structures of binary complexes of mammalian MSL3 and the histone acetyltransferase (HAT) MOF with consecutive segments of MSL1. MSL1 interacts with MSL3 as an extended chain forming an extensive hydrophobic interface, whereas the MSL1-MOF interface involves electrostatic interactions between the HAT domain and a long helix of MSL1. This structure provides insights into the catalytic mechanism of MOF and enables us to show analogous interactions of MOF with NSL1. In Drosophila, selective disruption of Msl1 interactions with Msl3 or Mof severely affects Msl1 targeting to the body of dosage-compensated genes and several high-affinity sites, without affecting promoter binding. We propose that Msl1 acts as a scaffold for MSL complex assembly to achieve specific targeting to the X chromosome.

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Figure 1: Crystal structures of the MSL1–MSL3 and MSL1–MOF subcomplexes.
Figure 2: Structure of the MSL1–MOF complex.
Figure 3: Structure of the MSL1–MSL3 complex.
Figure 4: Acetylation activity of the MSL subcomplexes.
Figure 5: Mutagenesis of the MSL1 and NSL1 residues involved in MOF and MSL3 binding.
Figure 6: Drosophila Msl3 and Mof are required for efficient targeting of Msl1.

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Acknowledgements

We thank K. Dzeyk of EMBL Heidelberg and I. Berard of the Institut de Biologie Structurale (IBS) Grenoble for their help with mass spectrometry; the High Throughput Crystallisation Laboratory (HTX) group of EMBL Grenoble for performing initial screening crystallization trials; M. Jamin's group for help with the MALLS experiment; the European Synchrotron Radiation Facility (ESRF)-EMBL Joint Structural Biology Group for access to and assistance on the ESRF synchrotron beamlines; P. Tropberger from R. Schneider's laboratory (Max Planck Institute of Immunology, Freiburg) for providing nucleosomes; and D. Panne and members of both laboratories for critical reading of the manuscript. E.H. is a Darwin trust fellow.

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Author notes

  1. Erinc Hallacli, Herbert Holz, Juan Sanchez-Weatherby & Asifa Akhtar

    Present address: Present addresses: Max-Planck-Institut für Immunbiologie und Epigenetik, Freiburg im Breisgau, Germany (E.H., H.H., A.A.); Diamond Light Source Ltd., Didcot, UK (J.S.-W.).,

  2. Jan Kadlec and Erinc Hallacli: These authors contributed equally to this work.

Authors and Affiliations

  1. European Molecular Biology Laboratory, Grenoble, France

    Jan Kadlec, Michael Lipp, Juan Sanchez-Weatherby & Stephen Cusack

  2. Unit of Virus Host-Cell Interactions, Université Joseph Fouier–European Molecular Biology Laboratory–Centre National de la Recherche Scientifique (UJF-EMBL-CNRS), Unité Mixte Internationale 3265, Grenoble, France

    Jan Kadlec, Michael Lipp, Juan Sanchez-Weatherby & Stephen Cusack

  3. European Molecular Biology Laboratory, Heidelberg, Germany

    Erinc Hallacli, Herbert Holz & Asifa Akhtar

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Contributions

J.K., E.H., S.C. and A.A. designed the project and wrote the manuscript; J.K. and M.L. produced and crystallized the proteins; J.K. solved, refined and analyzed the structures, prepared and tested the mutants in vitro, and carried out HAT assays on the H4 peptide; J.S.-W. and J.K. performed dehydration of MSL1–MSL3 crystals; H.H. performed HAT assays on nucleosomes; and E.H. carried out all in vivo experiments.

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Correspondence to Stephen Cusack or Asifa Akhtar.

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The authors declare no competing financial interests.

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Supplementary Figures 1–14, Supplementary Table 1 and Supplementary Methods (PDF 1551 kb)

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Kadlec, J., Hallacli, E., Lipp, M. et al. Structural basis for MOF and MSL3 recruitment into the dosage compensation complex by MSL1. Nat Struct Mol Biol 18, 142–149 (2011). https://doi.org/10.1038/nsmb.1960

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