2. Academic Validation
  3. A Tail-Based Mechanism Drives Nucleosome Demethylation by the LSD2/NPAC Multimeric Complex

A Tail-Based Mechanism Drives Nucleosome Demethylation by the LSD2/NPAC Multimeric Complex

  • Cell Rep. 2019 Apr 9;27(2):387-399.e7. doi: 10.1016/j.celrep.2019.03.061.
Chiara Marabelli 1,  Biagina Marrocco 1,  Simona Pilotto 1,  Sagar Chittori 2,  Sarah Picaud 3,  Sara Marchese 1,  Giuseppe Ciossani 1,  Federico Forneris 1,  Panagis Filippakopoulos 3,  Guy Schoehn 4,  Daniela Rhodes 5,  Sriram Subramaniam 6,  Andrea Mattevi 7
Affiliations

Affiliations

  • 1 Department of Biology and Biotechnology "Lazzaro Spallanzani," University of Pavia, via Ferrata 9, 27100 Pavia, Italy.
  • 2 Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  • 3 Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.
  • 4 Institut de Biologie Structurale (IBS), University Grenoble Alpes, CEA, CNRS, 38044 Grenoble, France.
  • 5 Institute of Structural Biology, Nanyang Technological University, 59 Nanyang Drive, Singapore 636921, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, Singapore 636921, Singapore.
  • 6 The University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada. Electronic address: sriram.subramaniam@ubc.ca.
  • 7 Department of Biology and Biotechnology "Lazzaro Spallanzani," University of Pavia, via Ferrata 9, 27100 Pavia, Italy. Electronic address: andrea.mattevi@unipv.it.
PMID: 30970244 DOI: 10.1016/j.celrep.2019.03.061
Abstract

LSD1 and LSD2 are homologous histone demethylases with opposite biological outcomes related to chromatin silencing and transcription elongation, respectively. Unlike LSD1, LSD2 nucleosome-demethylase activity relies on a specific linker peptide from the multidomain protein NPAC. We used single-particle cryoelectron microscopy (cryo-EM), in combination with kinetic and mutational analysis, to analyze the mechanisms underlying the function of the human LSD2/NPAC-linker/nucleosome complex. Weak interactions between LSD2 and DNA enable multiple binding modes for the association of the demethylase to the nucleosome. The demethylase thereby captures mono- and dimethyl Lys4 of the H3 tail to afford histone demethylation. Our studies also establish that the dehydrogenase domain of NPAC serves as a catalytically inert oligomerization module. While LSD1/CoREST forms a nucleosome docking platform at silenced gene promoters, LSD2/NPAC is a multifunctional Enzyme complex with flexible linkers, tailored for rapid chromatin modification, in conjunction with the advance of the RNA polymerase on actively transcribed genes.

Keywords

chromatin reader; cryoelectron microscopy; epigenetics; evolution of protein function; flavoenzyme; histone demethylation; molecular recognition.

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