ArticleJournal of molecular biology2014
A non-active-site SET domain surface crucial for the interaction of MLL1 and the RbBP5/Ash2L heterodimer within MLL family core complexes.
Article in Journal of molecular biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 50 citations in OpenAlex.
- Lysine methylation signaling in skeletal muscle biology: from myogenesis to clinical insights.The Biochemical journal · 2023Review
- Hierarchical assembly of the MLL1 core complex regulates H3K4 methylation and is dependent on temperature and component concentration.The Journal of biological chemistry · 2023Article
- Parallel functional annotation of cancer-associated missense mutations in histone methyltransferases.Scientific reports · 2022Article
- Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Review
- Kinetics of the multitasking high-affinity Win binding site of WDR5 in restricted and unrestricted conditions.The Biochemical journal · 2021Article
- Regulators of H3K4 methylation mutated in neurodevelopmental disorders control axon guidance inDevelopment (Cambridge, England) · 2020Article
- KMT2C/D COMPASS complex-associated diseases [KClinical epigenetics · 2020Review
- Structural Basis of H2B Ubiquitination-Dependent H3K4 Methylation by COMPASS.Molecular cell · 2019Article
- Kabuki syndrome: review of the clinical features, diagnosis and epigenetic mechanisms.World journal of pediatrics : WJP · 2019Review
- Identification of the Regulatory Elements and Target Genes of Megakaryopoietic Transcription Factor MEF2C.Thrombosis and haemostasis · 2019Article
- A comparative analysis of KMT2D missense variants in Kabuki syndrome, cancers and the general population.Journal of human genetics · 2019Article
- Dissecting KMT2D missense mutations in Kabuki syndrome patients.Human molecular genetics · 2018Article
- Article
- Chemical and Biochemical Perspectives of Protein Lysine Methylation.Chemical reviews · 2018Review
- Effect of high WDR5 expression on the hepatocellular carcinoma prognosis.Oncology letters · 2018Article
- Expanding the Oro-Dental and Mutational Spectra of Kabuki Syndrome and Expression ofInternational journal of biological sciences · 2018Article
- Writing, erasing and reading histone lysine methylations.Experimental & molecular medicine · 2017Review
- Somatic cancer mutations in the MLL1 histone methyltransferase modulate its enzymatic activity and dependence on the WDR5/RBBP5/ASH2L complex.Molecular oncology · 2017Article
- Diverse roles of WDR5-RbBP5-ASH2L-DPY30 (WRAD) complex in the functions of the SET1 histone methyltransferase family.Journal of biosciences · 2017Review
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
The mixed lineage leukemia-1 (MLL1) enzyme is a histone H3 lysine 4 (H3K4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human SET1 family of enzymes that include MLL1-MLL4 and SETd1a,b. Dimethylation of H3K4 requires a sub-complex including WRAD (WDR5, RbBP5, Ash2L, and DPY-30), which binds to each SET1 family member forming a minimal core complex that is required for multiple lysine methylation. We recently demonstrated that WRAD is a novel histone methyltransferase that preferentially catalyzes H3K4 dimethylation in a manner that is dependent on an unknown non-active-site surface from the MLL1 SET domain. Recent genome sequencing studies have identified a number of human disease-associated missense mutations that localize to the SET domains of several MLL family members. In this investigation, we mapped many of these mutations onto the three-dimensional structure of the SET domain and noticed that a subset of MLL2 (KMT2D, ALR, MLL4)-associated Kabuki syndrome missense mutations map to a common solvent-exposed surface that is not expected to alter enzymatic activity. We introduced these mutations into the MLL1 SET domain and observed that all are defective for H3K4 dimethylation by the MLL1 core complex, which is associated with a loss of the ability of MLL1 to interact with WRAD or with the RbBP5/Ash2L heterodimer. Our results suggest that amino acids from this surface, which we term the Kabuki interaction surface or KIS, are required for formation of a second active site within SET1 family core complexes.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.