Reactome | Formation of the MLL1 complex

Formation of the MLL1 complex

Stable Identifier

R-HSA-9675026

Type

Reaction [binding]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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Cleaved KMT2A (also known as MLL1) dimers bind the WRAD complex, composed of WDR5, RBBP5, ASH2L and DPY30, to form the MLL1 complex. As RBBP5, KMT2A also binds the beta-propeller domain of WDR5; however, KMT2A's binding sites are opposite to RBBP5's binding site on this domain (Avdic, Zhang, Lanouette, Groulx et al. 2011). KMT2A interacts with WDR5 through the WDR5 Interaction (WIN) motif. The conformation of the WIN motif is stabilized by two intramolecular hydrogen bonds, and the arginine R3765 is critical for KMT2A's interaction with WDR5 (Karatas et al. 2010; Dou et al. 2006; Patel, Dharmarajan and Cosgrove 2008; Patel, Vought et al. 2008; Shinsky et al. 2014). The interaction of KMT2A with WDR5 is fine-tuned by the simultaneous interaction of WDR5 with histone H3 (Avdic, Zhang, Lanouette, Vornova et al. 2011).

Histone H3 lysine 4 (H3K4) methyltransferase activity of KMT2A dramatically increases upon binding to the WRAD subcomplex (Patel et al. 2009, Patel et al. 2011, Dharmarajan et al. 2012). WDR5 facilitates the presentation of lysine K5 of histone H3 (K4 of the mature H3) for methylation by MLL histone methyltransferases although WDR5 does not directly interpret the methylation state (Ruthenburg et al. 2006). An intrapeptide interaction between the WD40 beta-propeller domain and the C-terminal distal region of RBBP5 contributes to the maintenance of the compact conformation of the MLL1 complex, while a vertebrate-specific motif in the C-terminal distal region of RBBP5 facilitates nucleosome recognition and methylation by the MLL1 complex (Han et al. 2019). Binding of RBBP5 to ubiquitin conjugated to histone H2B may facilitate the association of the MLL1 complex with the nucleosomes (Xue et al. 2019). RBBP5 and ASH2L are important for repositioning of the SET domain of KMT2A to form a well-ordered active site (Southall et al. 2009). DPY30, through interacting with and regulating ASH2L, restricts the rotational dynamics of the MLL1 complex on nucleosomes, promoting productive H3K4 methylation, especially at higher methylation states (i.e. H3K4me3 and H3K4me2) (Lee et al. 2021).

KMT2A has been reported to interact with the WD40 beta-propeller domain of RBBP5 through its catalytic SET domain, and the minimal active MLL1 complex consisting of the KMT2A, WDR5 and RBBP5 heterotrimer has been indicated (Kaustov et al. 2019).

Somatic mutations in KMT2A are often observed in cancer and have been shown to affect the catalytic activity of KMT2A, dependency on the WRAD complex, and sensitivity to inhibitors that block the interaction between KMT2A and WDR5 (Weirich et al. 2017).

Literature References

PubMed ID	Title	Journal	Year
31544921	The internal interaction in RBBP5 regulates assembly and activity of MLL1 methyltransferase complex Wang, X, Xu, Y, Li, M, Han, J, Li, Y, Su, C, Li, Y, Peng, C, Chen, Y, Li, N, Li, T	Nucleic Acids Res	2019
21135039	Fine-tuning the stimulation of MLL1 methyltransferase activity by a histone H3-based peptide mimetic Lanouette, S, Couture, JF, Avdic, V, Skerjanc, I, Zhang, P, Voronova, A	FASEB J	2011
28182322	Somatic cancer mutations in the MLL1 histone methyltransferase modulate its enzymatic activity and dependence on the WDR5/RBBP5/ASH2L complex Weirich, S, Jeltsch, A, Kudithipudi, S	Mol Oncol	2017
31400120	The MLL1 trimeric catalytic complex is a dynamic conformational ensemble stabilized by multiple weak interactions Kaustov, L, Aebersold, R, Vedadi, M, Li, F, Fang, X, Lemak, A, Faini, M, Wu, H, Wei, Y, Allali-Hassani, A, Arrowsmith, CH, Houliston, S, Fan, L, Wang, Y, Zeng, H, Duan, S	Nucleic Acids Res	2019
18829459	Structure of WDR5 bound to mixed lineage leukemia protein-1 peptide Patel, A, Cosgrove, MS, Dharmarajan, V	J Biol Chem	2008
31485071	Structural basis of nucleosome recognition and modification by MLL methyltransferases Huang, J, Lei, M, Cao, M, Yuan, G, Li, Y, Xue, H, Zhu, G, Yao, T, Chen, Y	Nature	2019
21106533	A novel non-SET domain multi-subunit methyltransferase required for sequential nucleosomal histone H3 methylation by the mixed lineage leukemia protein-1 (MLL1) core complex Patel, A, Vought, VE, Cosgrove, MS, Dharmarajan, V	J. Biol. Chem.	2011
19187761	Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks Roe, SM, Wilson, JR, Southall, SM, Odho, Z, Wong, PS	Mol Cell	2009
20575550	Analysis of the binding of mixed lineage leukemia 1 (MLL1) and histone 3 peptides to WD repeat domain 5 (WDR5) for the design of inhibitors of the MLL1-WDR5 interaction Karatas, H, Bernard, D, Dou, Y, Townsend, EC, Wang, S	J Med Chem	2010
24680668	A non-active-site SET domain surface crucial for the interaction of MLL1 and the RbBP5/Ash2L heterodimer within MLL family core complexes Vought, VE, Hu, M, Bamshad, MJ, Cosgrove, MS, Shinsky, SA, Shendure, J, Ng, SB	J Mol Biol	2014
19556245	On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex Patel, A, Vought, VE, Cosgrove, MS, Dharmarajan, V	J. Biol. Chem.	2009
16829959	Histone H3 recognition and presentation by the WDR5 module of the MLL1 complex Li, H, Wang, W, Graybosch, DM, Patel, DJ, Ruthenburg, AJ, Verdine, GL, Allis, CD	Nat. Struct. Mol. Biol.	2006
18829457	A conserved arginine-containing motif crucial for the assembly and enzymatic activity of the mixed lineage leukemia protein-1 core complex Patel, A, Vought, VE, Cosgrove, MS, Dharmarajan, V	J Biol Chem	2008
34012049	Mechanism for DPY30 and ASH2L intrinsically disordered regions to modulate the MLL/SET1 activity on chromatin Xu, J, Ayoub, A, Park, SH, Mao, F, Zheng, W, Cho, US, Zhang, Y, Dou, Y, Lee, YT, Sha, L	Nat Commun	2021
16878130	Regulation of MLL1 H3K4 methyltransferase activity by its core components Lee, JW, Roeder, RG, Milne, TA, Dou, Y, Ruthenburg, AJ, Verdine, GL, Lee, S, Allis, CD	Nat. Struct. Mol. Biol.	2006
22665483	Structural basis for WDR5 interaction (Win) motif recognition in human SET1 family histone methyltransferases Skalnik, DG, Patel, A, Cosgrove, MS, Dharmarajan, V, Lee, JH	J. Biol. Chem.	2012
21220120	Structural and biochemical insights into MLL1 core complex assembly Lanouette, S, Groulx, A, Couture, JF, Avdic, V, Zhang, P, Brunzelle, J, Tremblay, V	Structure	2011