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Title | A Tail-Based Mechanism Drives Nucleosome Demethylation by the LSD2/NPAC Multimeric Complex. |
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Journal, issue, pages | Cell Rep, Vol. 27, Issue 2, Page 387-399.e7, Year 2019 |
Publish date | Apr 9, 2019 |
Authors | Chiara Marabelli / Biagina Marrocco / Simona Pilotto / Sagar Chittori / Sarah Picaud / Sara Marchese / Giuseppe Ciossani / Federico Forneris / Panagis Filippakopoulos / Guy Schoehn / Daniela Rhodes / Sriram Subramaniam / Andrea Mattevi / |
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 ...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. |
External links | Cell Rep / PubMed:30970244 |
Methods | SAS (X-ray synchrotron) / EM (single particle) |
Resolution | 4.02 - 7.95 Å |
Structure data | SASDFU3: Lysine-specific Demethylase (LSD2) (Lysyne-specific Demethylase LSD2, LSD2) SASDFV3: Cytokine-like nuclear factor dehydrogenase domain, NPAC DH (NPAC delta-261) SASDFW3: Cytokine-like nuclear factor dehydrogenase domain, NPAC DH, plus native linker (NPAC delta-205) EMDB-4704, PDB-6r1t: EMDB-4705, PDB-6r1u: EMDB-4710, PDB-6r25: EMDB-4711: EMDB-4712: |
Chemicals | ChemComp-FAD: ChemComp-ZN: ChemComp-HOH: |
Source |
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Keywords | GENE REGULATION / Histone demethylation / chromatin reader / flavoenzyme / epigenetics / evolution of protein function / molecular recognition. |