A tail-based mechanism drives nucleosome demethylation by the LSD2/NPAC multimeric complex
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-parti...
| Main Authors: | , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2019
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| Online Access: | https://hdl.handle.net/10356/93135 http://hdl.handle.net/10220/48524 |
| _version_ | 1811685003597185024 |
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| author | Marabelli, Chiara Marrocco, Biagina Pilotto, Simona Chittori, Sagar Picaud, Sarah Marchese, Sara Ciossani, Giuseppe Forneris, Federico Filippakopoulos, Panagis Schoehn, Guy Rhodes, Daniela Subramaniam, Sriram Mattevi, Andrea |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Marabelli, Chiara Marrocco, Biagina Pilotto, Simona Chittori, Sagar Picaud, Sarah Marchese, Sara Ciossani, Giuseppe Forneris, Federico Filippakopoulos, Panagis Schoehn, Guy Rhodes, Daniela Subramaniam, Sriram Mattevi, Andrea |
| author_sort | Marabelli, Chiara |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T04:37:37Z |
| format | Journal Article |
| id | ntu-10356/93135 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:37:37Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-10356/931352020-11-01T05:18:27Z A tail-based mechanism drives nucleosome demethylation by the LSD2/NPAC multimeric complex Marabelli, Chiara Marrocco, Biagina Pilotto, Simona Chittori, Sagar Picaud, Sarah Marchese, Sara Ciossani, Giuseppe Forneris, Federico Filippakopoulos, Panagis Schoehn, Guy Rhodes, Daniela Subramaniam, Sriram Mattevi, Andrea School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) NTU Institute of Structural Biology Histone Demethylation Cryoelectron Microscopy DRNTU::Science::Biological sciences 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. Published version 2019-06-03T08:29:20Z 2019-12-06T18:34:31Z 2019-06-03T08:29:20Z 2019-12-06T18:34:31Z 2019 Journal Article Marabelli, C., Marrocco, B., Pilotto, S., Chittori, S., Picaud, S., Marchese, S., . . . Mattevi, A. (2019). A tail-based mechanism drives nucleosome demethylation by the LSD2/NPAC multimeric complex. Cell Reports, 27(2), 387-399. doi:10.1016/j.celrep.2019.03.061 2211-1247 https://hdl.handle.net/10356/93135 http://hdl.handle.net/10220/48524 10.1016/j.celrep.2019.03.061 en Cell Reports © 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 21 p. application/pdf |
| spellingShingle | Histone Demethylation Cryoelectron Microscopy DRNTU::Science::Biological sciences Marabelli, Chiara Marrocco, Biagina Pilotto, Simona Chittori, Sagar Picaud, Sarah Marchese, Sara Ciossani, Giuseppe Forneris, Federico Filippakopoulos, Panagis Schoehn, Guy Rhodes, Daniela Subramaniam, Sriram Mattevi, Andrea A tail-based mechanism drives nucleosome demethylation by the LSD2/NPAC multimeric complex |
| title | A tail-based mechanism drives nucleosome demethylation by the LSD2/NPAC multimeric complex |
| title_full | A tail-based mechanism drives nucleosome demethylation by the LSD2/NPAC multimeric complex |
| title_fullStr | A tail-based mechanism drives nucleosome demethylation by the LSD2/NPAC multimeric complex |
| title_full_unstemmed | A tail-based mechanism drives nucleosome demethylation by the LSD2/NPAC multimeric complex |
| title_short | A tail-based mechanism drives nucleosome demethylation by the LSD2/NPAC multimeric complex |
| title_sort | tail based mechanism drives nucleosome demethylation by the lsd2 npac multimeric complex |
| topic | Histone Demethylation Cryoelectron Microscopy DRNTU::Science::Biological sciences |
| url | https://hdl.handle.net/10356/93135 http://hdl.handle.net/10220/48524 |
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