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Details on Person Cleaved KMT2A (also known as MLL1) dimers bind the WRAD comp...
| Class:Id | Summation:9675704 |
|---|---|
| _displayName | Cleaved KMT2A (also known as MLL1) dimers bind the WRAD comp... |
| _timestamp | 2023-02-13 15:57:49 |
| created | [InstanceEdit:9675717] Orlic-Milacic, Marija, 2020-02-04 |
| modified | [InstanceEdit:9675722] Orlic-Milacic, Marija, 2020-02-04 [InstanceEdit:9818079] Orlic-Milacic, Marija, 2022-10-12 [InstanceEdit:9821613] Orlic-Milacic, Marija, 2022-12-09 [InstanceEdit:9822252] Orlic-Milacic, Marija, 2022-12-22 [InstanceEdit:9823259] Orlic-Milacic, Marija, 2023-01-04 [InstanceEdit:9823551] Orlic-Milacic, Marija, 2023-01-06 [InstanceEdit:9823554] Orlic-Milacic, Marija, 2023-01-06 [InstanceEdit:9828083] Orlic-Milacic, Marija, 2023-02-10 [InstanceEdit:9828117] Orlic-Milacic, Marija, 2023-02-10 [InstanceEdit:9828341] Orlic-Milacic, Marija, 2023-02-13 [InstanceEdit:9828342] Orlic-Milacic, Marija, 2023-02-13 |
| text | 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). |
| (summation) | [Reaction:9675026] Formation of the MLL1 complex [Homo sapiens] |
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