Marabelli, C; Marrocco, B; Pilotto, S; Chittori, S; Picaud, S; Marchese, S; Ciossani, G; ... Mattevi, A; + view all Marabelli, C; Marrocco, B; Pilotto, S; Chittori, S; Picaud, S; Marchese, S; Ciossani, G; Forneris, F; Filippakopoulos, P; Schoehn, G; Rhodes, D; Subramaniam, S; Mattevi, A; - view fewer (2019) A Tail-Based Mechanism Drives Nucleosome Demethylation by the LSD2/NPAC Multimeric Complex. Cell Reports , 27 (2) pp. 387-399. 10.1016/j.celrep.2019.03.061.

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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.

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