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-Structure paper
Title | Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome. |
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Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 119, Issue 38, Page e2205691119, Year 2022 |
Publish date | Sep 20, 2022 |
Authors | Sanim Rahman / Niklas A Hoffmann / Evan J Worden / Marissa L Smith / Kevin E W Namitz / Bruce A Knutson / Michael S Cosgrove / Cynthia Wolberger / |
PubMed Abstract | 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 ...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, DR5, bBp5, sh2L, and PY-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. |
External links | Proc Natl Acad Sci U S A / PubMed:36095189 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.35 - 4.65 Å |
Structure data | EMDB-26454, PDB-7ud5: EMDB-27715, PDB-8du4: EMDB-27802: Complex between MLL1-WRAD and an H2B-ubiquitinated nucleosome- State 1 EMDB-27803: Complex between MLL1-WRAD and an H2B-ubiquitinated nucleosome- State 3 |
Chemicals | ChemComp-SAH: ChemComp-ZN: |
Source |
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Keywords | DNA BINDING PROTEIN / ubiquitin / chromatin / MLL / methylation |