Histone H3 recognition and presentation by the WDR5 module of the MLL1 complex

Ruthenburg, Alexander J.; Wang, Wooikoon; Graybosch, Daina M.; Li, Haitao; Allis, C. David; Patel, Dinshaw J.; Verdine, Gregory L.

doi:10.1038/nsmb1119

Cited by 221 publications

(236 citation statements)

References 53 publications

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“…We determined a K d of 1.6 μM for the interaction of WDR5 with L-H3, which is in good agreement with previous reports. 35,38 Under the same experimental conditions, we could not detect any interaction with D-H3 (Figure 4c).…”

Section: ■ Results and Discussionmentioning

confidence: 74%

Analysis of Phosphorylation-Dependent Protein–Protein Interactions of Histone H3

Klingberg¹,

Jost

Schümann³

et al. 2014

ACS Chem. Biol.

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Multiple posttranslational modifications (PTMs) of histone proteins including site-specific phosphorylation of serine and threonine residues govern the accessibility of chromatin. According to the histone code theory, PTMs recruit regulatory proteins or block their access to chromatin. Here, we report a general strategy for simultaneous analysis of both of these effects based on a SILAC MS scheme. We applied this approach for studying the biochemical role of phosphorylated S10 of histone H3. Differential pull-down experiments with H3-tails synthesized from L-and D-amino acids uncovered that histone acetyltransferase 1 (HAT1) and retinoblastoma-binding protein 7 (RBBP7) are part of the protein network, which interacts with the unmodified H3-tail. An additional H3-derived bait containing the nonhydrolyzable phospho-serine mimic phosphonomethylenalanine (Pma) at S10 recruited several isoforms of the 14-3-3 family and blocked the recruitment of HAT1 and RBBP7 to the unmodified H3-tail. Our observations provide new insights into the many functions of H3S10 phosphorylation. In addition, the outlined methodology is generally applicable for studying specific binding partners of unmodified histone tails.

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Section: ■ Results and Discussionmentioning

confidence: 74%

Analysis of Phosphorylation-Dependent Protein–Protein Interactions of Histone H3

Klingberg¹,

Jost

Schümann³

et al. 2014

ACS Chem. Biol.

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“…6(C)]. 68 The recombination activating gene 2 contains a plant homeodomain that recognizes histone H3 methylated at Lys 5 and influences V(D)J recombination [ Fig. 6(D)].…”

Section: Examination Of the Morfs In Rnap II And Histone H3mentioning

confidence: 99%

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

et al. 2013

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Molecular recognition features (MoRFs) are intrinsically disordered protein regions that bind to partners via disorder-to-order transitions. In one-to-many binding, a single MoRF binds to two or more different partners individually. MoRF-based one-to-many protein-protein interaction (PPI) examples were collected from the Protein Data Bank, yielding 23 MoRFs bound to 2-9 partners, with all pairs of same-MoRF partners having less than 25% sequence identity. Of these, 8 MoRFs were bound to 2-9 partners having completely different folds, whereas 15 MoRFs were bound to 2-5 partners having the same folds but with low sequence identities. For both types of partner variation, backbone and side chain torsion angle rotations were used to bring about the conformational changes needed to enable close fits between a single MoRF and distinct partners. Alternative splicing events (ASEs) and posttranslational modifications (PTMs) were also found to contribute to distinct partner binding. Because ASEs and PTMs both commonly occur in disordered regions, and because both ASEs and PTMs are often tissue-specific, these data suggest that MoRFs, ASEs, and PTMs may collaborate to alter PPI networks in different cell types. These data enlarge the set of carefully studied MoRFs that use inherent flexibility and that also use ASE-based and/or PTM-based surface modifications to enable the same disordered segment to selectively associate with two or more partners. The small number of residues involved in MoRFs and in their modifications by ASEs or PTMs may simplify the evolvability of signaling network diversity.

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“…11,12,23 The amide group of 2 forms one direct and one water-mediated (W517) hydrogen bond with the side chain of S91 and the backbone nitrogen of C261, respectively. The N-methylpiperazine moiety, predicted to be significantly protonated at physiological pH, 27 forms a water-mediated (W576) hydrogen bond with the backbone carbonyl of C261, and it occupies the bottom of the pocket.…”

mentioning

confidence: 99%

Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction

Bolshan

Getlik

Kuznetsova

et al. 2013

ACS Med. Chem. Lett.

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The WD40-repeat protein WDR5 plays a critical role in maintaining the integrity of MLL complexes and fully activating their methyltransferase function. MLL complexes, the trithorax-like family of SET1 methyltransferases, catalyze trimethylation of lysine 4 on histone 3, and they have been widely implicated in various cancers. Antagonism of WDR5 and MLL subunit interaction by small molecules has recently been presented as a practical way to inhibit activity of the MLL1 complex, and N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides were reported as potent and selective antagonists of such an interaction. Here, we describe the protein crystal structure guided optimization of prototypic compound 2 (K dis = 7 μM), leading to identification of more potent antagonist 47 (K dis = 0.3 μM). KEYWORDS: WDR5, MLL, SET1 methyltransferase complex, peptide binding site, small molecule antagonists T he SET1-family of human histone methyltransferases (SET1A, SET1B, MLL1, MLL2, MLL3, and MLL4) contribute to active chromatin via mono-, di-, and trimethylation of lysine 4 on histone H3. 1−3 MLLs are S-adenosyl methionine (SAM) dependent lysine methyltransferases that work optimally when in complex with other components; WDR5 (WD40 repeat protein 5), RbBP5 (retinoblastomabinding protein-5), ASH2L (absent small homeotic disks-2-like), and DPY-30 (WRAD). 4 WDR5 has been shown to be essential for complex integrity and for fully activating MLL methyltransferase function. 5−7 In the peptide-bound structure, WDR5 adopts a donutshaped WD40-repeat fold with a deep central cavity that normally accommodates an arginine side chain of interacting peptides. 8 WDR5 binds to the "WDR5 INteracting" (WIN) motif of MLL1 through the peptidyl arginine-binding cleft. 8−12 A crystal structure of WDR5 in complex with MLL1 WIN peptide revealed the critical role of arginine 3765 of MLL1 in complex formation. 9 A similar interaction has been reported for WDR5 and the WIN region of all SET1 family lysine methyltransferases, with reported K D values of 1.13, 0.16, 2.03, 0.03, 0.26, and 0.10 μM for MLL1-4, SET1A, and SET1B WIN peptides, respectively. 13 Although there is significant divergence in the amino acid sequences of WIN motifs close to the critical arginine residue, the plasticity of the WDR5 arginine binding pocket allows such an interaction with the WIN motifs of all MLLs. 13 MLLs have been reported to be essential for embryonic development and biological processes 14−17 and have been widely implicated in a variety of cancers. 18−22 As almost all MLLs show minimal or no activity in the absence of the complex components (WDR5 in particular), 13 identifying WDR5−MLL interaction antagonists has been proposed as a potentially selective alternative to active site directed inhibitors of MLL methyltransferase activity. Such antagonists could serve as a starting point for the development of potential therapeutics to treat MLL-rearranged leukemias or other related cancers. 23 Recent reports detailing the use of short arginine contain...

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Histone H3 recognition and presentation by the WDR5 module of the MLL1 complex

Cited by 221 publications

References 53 publications

Analysis of Phosphorylation-Dependent Protein–Protein Interactions of Histone H3

Analysis of Phosphorylation-Dependent Protein–Protein Interactions of Histone H3

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction

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