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A tail-based mechanism drives nucleosome demethylation by the LSD2/NPAC multimeric complex

DOI: 10.1016/j.celrep.2019.03.061 DOI Help

Authors: Chiara Marabelli (University of Pavia) , Biagina Marrocco (University of Pavia) , Simona Pilotto (University of Pavia) , Sagar Chittori (National Cancer Institute, NIH) , Sarah Picaud (Structural Genomics Consortium, University of Oxford) , Sara Marchese (University of Pavia) , Giuseppe Ciossani (University of Pavia) , Federico Forneris (University of Pavia) , Panagis Filippakopoulos (Structural Genomics Consortium, University of Oxford) , Guy Schoehn (Institut de Biologie Structurale (IBS), University Grenoble Alpes) , Daniela Rhodes (Institute of Structural Biology, Nanyang Technological University; Nanyang Technological University) , Sriram Subramaniam (The University of British Columbia) , Andrea Mattevi (University of Pavia)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Reports , VOL 27 , PAGES 387 - 399.e7

State: Published (Approved)
Published: April 2019
Diamond Proposal Number(s): 16082

Open Access Open Access

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

Subject Areas: Biology and Bio-materials

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