6r25 | pdb_00006r25
Structure of LSD2/NPAC-linker/nucleosome core particle complex: Class 3
Structural highlights
Function[KDM1B_HUMAN] Histone demethylase that demethylates 'Lys-4' of histone H3, a specific tag for epigenetic transcriptional activation, thereby acting as a corepressor. Required for de novo DNA methylation of a subset of imprinted genes during oogenesis. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Demethylates both mono- and di-methylated 'Lys-4' of histone H3. Has no effect on tri-methylated 'Lys-4', mono-, di- or tri-methylated 'Lys-9', mono-, di- or tri-methylated 'Lys-27', mono-, di- or tri-methylated 'Lys-36' of histone H3, or on mono-, di- or tri-methylated 'Lys-20' of histone H4 (By similarity). Publication Abstract from PubMedLSD1 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. A Tail-Based Mechanism Drives Nucleosome Demethylation by the LSD2/NPAC Multimeric Complex.,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 Cell Rep. 2019 Apr 9;27(2):387-399.e7. doi: 10.1016/j.celrep.2019.03.061. PMID:30970244[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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