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Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome
The human Mixed Lineage Leukemia-1 (MLL1) complex methylates histone H3K4 to promote transcription and is stimulated by monoubiquitination of histone H2B. Recent structures of the MLL1-WRAD core complex, which comprises the MLL1 methyltransferase, WDR5, RbBp5, Ash2L, and DPY-30, have revealed variab...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499523/ https://www.ncbi.nlm.nih.gov/pubmed/36095189 http://dx.doi.org/10.1073/pnas.2205691119 |
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author | Rahman, Sanim Hoffmann, Niklas A. Worden, Evan J. Smith, Marissa L. Namitz, Kevin E. W. Knutson, Bruce A. Cosgrove, Michael S. Wolberger, Cynthia |
author_facet | Rahman, Sanim Hoffmann, Niklas A. Worden, Evan J. Smith, Marissa L. Namitz, Kevin E. W. Knutson, Bruce A. Cosgrove, Michael S. Wolberger, Cynthia |
author_sort | Rahman, Sanim |
collection | PubMed |
description | The human Mixed Lineage Leukemia-1 (MLL1) complex methylates histone H3K4 to promote transcription and is stimulated by monoubiquitination of histone H2B. Recent structures of the MLL1-WRAD core complex, which comprises the MLL1 methyltransferase, WDR5, RbBp5, Ash2L, and DPY-30, have revealed variability in the docking of MLL1-WRAD on nucleosomes. In addition, portions of the Ash2L structure and the position of DPY30 remain ambiguous. We used an integrated approach combining cryoelectron microscopy (cryo-EM) and mass spectrometry cross-linking to determine a structure of the MLL1-WRAD complex bound to ubiquitinated nucleosomes. The resulting model contains the Ash2L intrinsically disordered region (IDR), SPRY insertion region, Sdc1-DPY30 interacting region (SDI-motif), and the DPY30 dimer. We also resolved three additional states of MLL1-WRAD lacking one or more subunits, which may reflect different steps in the assembly of MLL1-WRAD. The docking of subunits in all four states differs from structures of MLL1-WRAD bound to unmodified nucleosomes, suggesting that H2B-ubiquitin favors assembly of the active complex. Our results provide a more complete picture of MLL1-WRAD and the role of ubiquitin in promoting formation of the active methyltransferase complex. |
format | Online Article Text |
id | pubmed-9499523 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-94995232022-09-23 Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome Rahman, Sanim Hoffmann, Niklas A. Worden, Evan J. Smith, Marissa L. Namitz, Kevin E. W. Knutson, Bruce A. Cosgrove, Michael S. Wolberger, Cynthia Proc Natl Acad Sci U S A Biological Sciences The human Mixed Lineage Leukemia-1 (MLL1) complex methylates histone H3K4 to promote transcription and is stimulated by monoubiquitination of histone H2B. Recent structures of the MLL1-WRAD core complex, which comprises the MLL1 methyltransferase, WDR5, RbBp5, Ash2L, and DPY-30, have revealed variability in the docking of MLL1-WRAD on nucleosomes. In addition, portions of the Ash2L structure and the position of DPY30 remain ambiguous. We used an integrated approach combining cryoelectron microscopy (cryo-EM) and mass spectrometry cross-linking to determine a structure of the MLL1-WRAD complex bound to ubiquitinated nucleosomes. The resulting model contains the Ash2L intrinsically disordered region (IDR), SPRY insertion region, Sdc1-DPY30 interacting region (SDI-motif), and the DPY30 dimer. We also resolved three additional states of MLL1-WRAD lacking one or more subunits, which may reflect different steps in the assembly of MLL1-WRAD. The docking of subunits in all four states differs from structures of MLL1-WRAD bound to unmodified nucleosomes, suggesting that H2B-ubiquitin favors assembly of the active complex. Our results provide a more complete picture of MLL1-WRAD and the role of ubiquitin in promoting formation of the active methyltransferase complex. National Academy of Sciences 2022-09-12 2022-09-20 /pmc/articles/PMC9499523/ /pubmed/36095189 http://dx.doi.org/10.1073/pnas.2205691119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Rahman, Sanim Hoffmann, Niklas A. Worden, Evan J. Smith, Marissa L. Namitz, Kevin E. W. Knutson, Bruce A. Cosgrove, Michael S. Wolberger, Cynthia Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome |
title | Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome |
title_full | Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome |
title_fullStr | Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome |
title_full_unstemmed | Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome |
title_short | Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome |
title_sort | multistate structures of the mll1-wrad complex bound to h2b-ubiquitinated nucleosome |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499523/ https://www.ncbi.nlm.nih.gov/pubmed/36095189 http://dx.doi.org/10.1073/pnas.2205691119 |
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