Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The WD40 repeat protein WDR5 specifically associates with the K4-methylated histone H3 in human cells. To investigate the structural basis for this specific recognition, we have determined the structure of WDR5 in complex with a dimethylated H3-K4 peptide at 1.9 A resolution. Unlike the chromodomain that recognizes the methylated H3-K4 through a hydrophobic cage, the specificity of WDR5 for methylated H3-K4 is conferred by the nonconventional hydrogen bonds between the two zeta-methyl groups of the dimethylated Lys4 and the carboxylate oxygen of Glu322 in WDR5. The three amino acids Ala-Arg-Thr preceding Lys4 form most of the specific contacts with WDR5, with Ala1 forming intermolecular hydrogen bonds and salt bridges, and the side chain of Arg2 inserting into the central channel of WDR5. Both structural and biochemical studies presented here suggest another mode of recognition for the methylated histone tail.
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PMID:Structural basis for the specific recognition of methylated histone H3 lysine 4 by the WD-40 protein WDR5. 1660 Aug 77

We determined the three-dimensional structure of the PHD finger of the rice Siz/PIAS-type SUMO ligase, OsSiz1, by NMR spectroscopy and investigated binding ability for a variety of methylated histone H3 tails, showing that OsSiz1-PHD primarily recognizes dimethylated Arg2 of the histone H3 and that methylations at Arg2 and Lys4 reveal synergy effect on binding to OsSiz1-PHD. The K4 cage of OsSiz1-PHD for trimethylated Lys4 of H3K4me3 was similar to that of the BPTF-PHD finger, while the R2 pocket for Arg2 was different. It is intriguing that the PHD module of Siz/PIAS plays an important role, with collaboration with the DNA binding domain SAP, in gene regulation through SUMOylation of a variety of effectors associated with the methylated arginine-riched chromatin domains.
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PMID:PHD finger of the SUMO ligase Siz/PIAS family in rice reveals specific binding for methylated histone H3 at lysine 4 and arginine 2. 2262 55

Microrchidia (MORC) proteins are GHKL (gyrase, heat-shock protein 90, histidine kinase, MutL) ATPases that function in gene regulation in multiple organisms. Animal MORCs also contain CW-type zinc finger domains, which are known to bind to modified histones. We solved the crystal structure of the murine MORC3 ATPase-CW domain bound to the nucleotide analog AMPPNP (phosphoaminophosphonic acid-adenylate ester) and in complex with a trimethylated histone H3 lysine 4 (H3K4) peptide (H3K4me3). We observed that the MORC3 N-terminal ATPase domain forms a dimer when bound to AMPPNP. We used native mass spectrometry to show that dimerization is ATP-dependent, and that dimer formation is enhanced in the presence of nonhydrolyzable ATP analogs. The CW domain uses an aromatic cage to bind trimethylated Lys4 and forms extensive hydrogen bonds with the H3 tail. We found that MORC3 localizes to promoters marked by H3K4me3 throughout the genome, consistent with its binding to H3K4me3 in vitro. Our work sheds light on aspects of the molecular dynamics and function of MORC3.
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PMID:Mouse MORC3 is a GHKL ATPase that localizes to H3K4me3 marked chromatin. 2752 81

During gene expression, histone acetylation by histone acetyltransferase (HAT) loosens the chromatin structure around the promoter to allow RNA polymerase II (Pol II) to initiate transcription, while de-acetylation by histone deacetylase (HDAC) tightens the structure in the transcribing region to repress false initiation. Histone acetylation is also regulated by intracellular pH (pHi) with global hypoacetylation observed at low pHi, and hyperacetylation, causing proliferation, observed at high pHi. However, the mechanism underlying the pHi-dependent regulation of gene expression remains elusive. Here, we have explored the role of the chromodomain (CD) of budding yeast Eaf3, a common subunit of both HAT and HDAC that is thought to recognize methylated lysine residues on histone H3. We found that Eaf3 CD interacts with histone H3 peptides methylated at Lys4 (H3K4me, a promoter epigenetic marker) and Lys36 (H3K36me, a coding region epigenetic marker), as well as with many dimethyl-lysine peptides and even arginine-asymmetrically dimethylated peptides, but not with unmethylated, phosphorylated or acetylated peptides. The Eaf3 CD structure revealed an unexpected histidine residue in the aromatic cage essential for binding H3K4me and H3K36me. pH titration experiments showed that protonation of the histidine residue around physiological pH controls the charge state of the aromatic cage to regulate binding to H3K4me and H3K36me. Histidine substitution and NMR experiments confirmed the correlation of histidine pKa with binding affinity. Collectively, our findings suggest that Eaf3 CD functions as a pHi sensor and a regulator of gene expression via its pHi-dependent interaction with methylated nucleosomes.
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PMID:The Eaf3 chromodomain acts as a pH sensor for gene expression by altering its binding affinity for histone methylated-lysine residues. 3203 Dec 6