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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...

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Autores principales: Rahman, Sanim, Hoffmann, Niklas A., Worden, Evan J., Smith, Marissa L., Namitz, Kevin E. W., Knutson, Bruce A., Cosgrove, Michael S., Wolberger, Cynthia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
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.
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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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