Structure of the SPRY domain of human Ash2L and its interactions with RbBP5 and DPY30

Chen, Yong; Cao, Fang; Wan, Bao-Fei; Dou, Yali; Lei, Ming

doi:10.1038/cr.2012.9

Cited by 44 publications

(54 citation statements)

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“…With prior studies showing that the Ash2L C4-WingedHelix (C4-WH) domain is important for binding to DNA (Chen et al 2011;Sarvan et al 2011) and ubiquitin (Wu et al 2013) and that its SDI motif is important for binding to DPY-30 (South et al 2010;Chen et al 2012), our results point to a model in which Ash2L acts as a modulatory platform enabling the integration of a cascade of binding events that ultimately lead to the precise regulation of KMT2 methyltransferase activity. Here we report that Ash2L also recognizes the phosphorylated form of RbBP5.…”

Section: Rbbp5 Phosphorylation: a Novel Regulatory Switch Controllingmentioning

confidence: 91%

“…In RbBP5, a predicted unstructured region binds to Ash2L and WDR5 and is important for the stimulation of MLL1 methyltransferase activity (Cao et al 2010;Avdic et al 2011). Furthermore, mapping analysis has identified that this region of RbBP5 binds to the SPIa and ryanodine receptor (SPRY) domain of Ash2L (Chen et al 2012); however, the structural basis underlying the interaction of RbBP5 with Ash2L is unknown.Here, we report the crystal structure of the Ash2L SPRY domain in complex with RbBP5. We show that Ash2L-RbBP5-binding specificity is conferred by several conserved residues on both Ash2L and RbBP5.…”

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confidence: 99%

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A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation

et al. 2015

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The methyltransferase activity of the trithorax group (TrxG) protein MLL1 found within its COMPASS (complex associated with SET1)-like complex is allosterically regulated by a four-subunit complex composed of WDR5, RbBP5, Ash2L, and DPY30 (also referred to as WRAD). We report structural evidence showing that in WRAD, a concave surface of the Ash2L SPIa and ryanodine receptor (SPRY) domain binds to a cluster of acidic residues, referred to as the D/E box, in RbBP5. Mutational analysis shows that residues forming the Ash2L/RbBP5 interface are important for heterodimer formation, stimulation of MLL1 catalytic activity, and erythroid cell terminal differentiation. We also demonstrate that a phosphorylation switch on RbBP5 stimulates WRAD complex formation and significantly increases KMT2 (lysine [K] methyltransferase 2) enzyme methylation rates. Overall, our findings provide structural insights into the assembly of the WRAD complex and point to a novel regulatory mechanism controlling the activity of the KMT2/COMPASS family of lysine methyltransferases.Supplemental material is available for this article.Received October 27, 2014; revised version accepted December 15, 2014. The methyltransferase activity of the trithorax group (TrxG) protein MLL1 as well as the other members of the KMT2 (lysine [K] methyltransferase 2) family found within COMPASS (complex associated with SET1) catalyzes the site-specific methylation of the e-amine of Lys4 (K4) of histone H3 (Shilatifard 2012). While these enzymes share the ability to methylate the same residue on histone H3, the catalytic activity of these enzymes is linked to different biological processes. MLL1/MLL2 di/trimethylate H3K4 (H3K4me2/3) and regulate Hox gene expression during embryonic development (Yu et al. 1995;Dou et al. 2006). MLL3/MLL4 regulate adipogenesis ) and primarily monomethylate H3K4 (H3K4me1) at both enhancer (Herz et al. 2012;Hu et al. 2013) and promoter (Cheng et al. 2014) regions, while SET1A/B are the primary H3K4 trimethyltransferases (Wu et al. 2008). However, despite divergence in catalytic activity and functional roles, enzymes of the KMT2/COMPASS family must assemble into multisubunit complexes to carry out their biological functions.Our molecular understanding of the protein complexes involved in H3K4 methylation stems from the isolation of COMPASS from Saccharomyces cerevisiae (Miller et al. 2001;Roguev et al. 2001;Krogan et al. 2002;Dehe et al. 2006). These studies demonstrated that regulatory subunits found within COMPASS and mammalian COMPASS-like complexes play key roles in stabilizing the enzyme and stimulating its methyltransferase activity as well as targeting the protein complex to specific genomic loci (Couture and Skiniotis 2013). While each of these multisubunit protein complexes contains unique subunits, each member of the KMT2 family associates with a common set of four evolutionarily conserved regulatory proteins; namely, WDR5, RbBP5, Ash2L, and DPY30 (WRAD) (Couture and Skiniotis 2013). The foursubunit complex directly binds ...

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Section: Rbbp5 Phosphorylation: a Novel Regulatory Switch Controllingmentioning

confidence: 91%

mentioning

confidence: 99%

A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation

et al. 2015

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“…Ash2l may be recruited to target genes through its association with transcription factors (56 -58) and MLL subunits such as Rbbp5, Dpy30, and Wdr5 (36). However, Rbbp5 and Wdr5 can also form protein complexes that are distinct from those containing Ash2l (34,37,55).…”

Section: Ash2l Is Important For Es Cell Pluripotency-thementioning

confidence: 99%

The Trithorax Group Protein Ash2l Is Essential for Pluripotency and Maintaining Open Chromatin in Embryonic Stem Cells

Wan

Liang

Xiong

et al. 2013

Journal of Biological Chemistry

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“…16,32 These in vivo findings were also recently supported by three independent studies with the human homologs, showing that ASH2L (Cps60) and DPY30 (Cps25) interact independently of MLL1. [33][34][35] Finally, recent studies in yeast COMPASS demonstrated that histone H2B monoubiquitination regulates the H3K4 mono-and di-methylation are now commonly known to be enriched in transcriptional enhancer elements at active and potentially active genes, respectively, while trimethylation of the same residue is a mark associated with the transcriptional start sites of actively transcribed genes. 10,11 Additional analysis of the COMPASS complex revealed that several of its protein subunits (Cps) were evolutionary conserved.…”

Section: Subunit Deletion: the First Approach To Dissect Protein Compmentioning

confidence: 99%

“…1A). 34 Overall, these structural studies have provided detailed information regarding the specificity of MLL1 complex formation and offered a better understanding of the regulation of MLL1 by the core complex Cps members. However, given that the recent structural studies have focused on protein/peptide complexes, the full extent of the interactions underlying the formation of the WRAD complex and its interaction with SET1 members has remained unclear.…”

Section: Where To Go From Herementioning

confidence: 99%

Assembling a COMPASS

Couture

Skiniotis

2013

Epigenetics

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P ost-translational modifications ofhistone proteins lie at the heart of the epigenetic landscape in the cell's nucleus and the precise regulation of gene expression. A myriad of studies have showed that several histone-modifying enzymes are controlled by modulatory protein partner subunits and other post-transcriptional modifications deposited in the vicinity of the targeted site. All together, these mechanisms create an intricate network of interactions that regulate enzymatic activities and ultimately control the site-specific deposition of covalent modifications. In this Point-of-View, we discuss our evolving understanding on the assembly and architecture of histone H3 Lys-4 (H3K4) methyltransferase COMPASS complexes and the techniques that progressively allowed us to better define the molecular basis of complex formation and function. We further briefly discuss some of the challenges lying ahead and additional approaches required to understand mechanistic details for the function of such complexes.

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Structure of the SPRY domain of human Ash2L and its interactions with RbBP5 and DPY30

Cited by 44 publications

References 10 publications

A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation

A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation

The Trithorax Group Protein Ash2l Is Essential for Pluripotency and Maintaining Open Chromatin in Embryonic Stem Cells

Assembling a COMPASS

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