6R25

Structure of LSD2/NPAC-linker/nucleosome core particle complex: Class 3

Summary for 6R25

• Entry DOI: 10.2210/pdb6r25/pdb
• EMDB information: 4710
• Descriptor: Lysine-specific histone demethylase 1B, FLAVIN-ADENINE DINUCLEOTIDE, ZINC ION, ... (12 entities in total)
• Functional Keywords: histone demethylation, chromatin reader, flavoenzyme, epigenetics, evolution of protein function, molecular recognition., gene regulation
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 13
• Total formula weight: 304538.97

Authors

Marabelli, C.,Pilotto, S.,Chittori, S.,Subramaniam, S.,Mattevi, A. (deposition date: 2019-03-15, release date: 2019-04-24)

Primary citation

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.
A Tail-Based Mechanism Drives Nucleosome Demethylation by the LSD2/NPAC Multimeric Complex.
Cell Rep, 27:387-399.e7, 2019

PubMed 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.

PubMed: 30970244
DOI: 10.1016/j.celrep.2019.03.061

Experimental method

ELECTRON MICROSCOPY (4.61 Å)