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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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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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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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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DOI: https://doi.org/10.1038/nsmb.1960
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