6qxz

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== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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The ASHH2 CW domain is responsible for recognizing the methylation state at lysine 4 of histone 3 N-terminal tails and implicated in the recruitment of the ASHH2 methyltransferase enzyme correctly to the histones. The ASHH2 CW domain binds H3 lysine motifs that can be either mono-, di-, or tri-methylated [ARTK(meX)QTAR, where X denotes the number of methylations], but binds strongest to monomethylated instances (Kd values reported in the range of 1 microm to 500 nM). Hoppmann et al. published the uncomplexed NMR structure of an ASHH2 CW domain in 2011. Here we document the assignment of a shortened ASHH2 CW construct, CW42, with similar binding affinity and better expression yields than the one used to solve the uncomplexed structure. We also perform (1)H-(15)N HSQC-monitored titrations that document at which protein-peptide ratios the complex is saturated. Backbone resonance assignments are presented for this shortened ASHH2 CW domain alone and bound to an H3 histone tail mimicking peptide monomethylated on lysine 4 (ARTK(me1)QTAR). Likewise, the assignment was also performed for the protein in complex with the dimethylated (ARTK(me2)QTAR) and trimethylated (ARTK(me3)QTAR) peptide. Overall, these two latter situations displayed a similar perturbation of shifts as the mono-methylated instance. In the case of the monomethylated histone tail mimic, side-chain assignment of CW42 in this complex was performed and reported in addition to backbone assignment, in preparation of a future solution structure determination and dynamics characterization of the CW42-ARTK(me1)QTAR complex.
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Chromatin post-translational modifications are thought to be important for epigenetic effects on gene expression. Methylation of histone N-terminal tail lysine residues constitutes one of many such modifications, executed by families of histone lysine methyltransferase (HKMTase). One such protein is ASHH2 from the flowering plant Arabidopsis thaliana, equipped with the interaction domain, CW, and the HKMTase domain, SET. The CW domain of ASHH2 is a selective binder of monomethylation at lysine 4 on histone H3 (H3K4me1) and likely helps the enzyme dock correctly onto chromatin sites. The study of CW and related interaction domains has so far been emphasizing lock-key models, missing important aspects of histone-tail CW interactions. We here present an analysis of the ASHH2 CW-H3K4me1 complex using NMR and molecular dynamics, as well as mutation and affinity studies of flexible coils. beta-augmentation and rearrangement of coils coincide with changes in the flexibility of the complex, in particular the eta1, eta3 and C-terminal coils, but also in the beta1 and beta2 strands and the C-terminal part of the ligand. Furthermore, we show that mutating residues with outlier dynamic behaviour affect the complex binding affinity despite these not being in direct contact with the ligand. Overall, the binding process is consistent with conformational selection. We propose that this binding mechanism presents an advantage when searching for the correct post-translational modification state among the highly modified and flexible histone tails, and also that the binding shifts the catalytic SET domain towards the nucleosome. DATABASES: Structural data are available in the PDB database under the accession code 6QXZ. Resonance assignments for CW42 in its apo- and holo-forms are available in the BMRB database under the accession code 27251.
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(1)H, (13)C, and (15)N resonance assignments of CW domain of the N-methyltransferase ASHH2 free and bound to the mono-, di- and tri-methylated histone H3 tail peptides.,Dobrovolska O, Bril'kov M, Odegard-Fougner O, Aasland R, Halskau O Biomol NMR Assign. 2018 Apr;12(1):215-220. doi: 10.1007/s12104-018-9811-x. Epub, 2018 Feb 16. PMID:29453713<ref>PMID:29453713</ref>
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The Arabidopsis (ASHH2) CW domain binds monomethylated K4 of the histone H3 tail through conformational selection.,Dobrovolska O, Brilkov M, Madeleine N, Odegard-Fougner O, Stromland O, Martin SR, De Marco V, Christodoulou E, Teigen K, Isaksson J, Underhaug J, Reuter N, Aalen RB, Aasland R, Halskau O FEBS J. 2020 Oct;287(20):4458-4480. doi: 10.1111/febs.15256. Epub 2020 Mar 24. PMID:32083791<ref>PMID:32083791</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Revision as of 10:50, 24 December 2020

Solution structure of the ASHH2 CW domain with the N-terminal histone H3 tail mimicking peptide monomethylated on lysine 4

PDB ID 6qxz

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