Structural highlights
Function
[EAF3_YEAST] Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of selected genes principally by acetylation of nucleosomal histone H4 and H2A. The NuA4 complex is also involved in DNA repair.[1] [2] [3]
Publication Abstract from PubMed
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.
The Eaf3 chromodomain acts as a pH sensor for gene expression by altering its binding affinity for histone methylated-lysine residues.,Okuda M, Nishimura Y Biosci Rep. 2020 Feb 28;40(2). pii: 222061. doi: 10.1042/BSR20191958. PMID:32031206[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Eisen A, Utley RT, Nourani A, Allard S, Schmidt P, Lane WS, Lucchesi JC, Cote J. The yeast NuA4 and Drosophila MSL complexes contain homologous subunits important for transcription regulation. J Biol Chem. 2001 Feb 2;276(5):3484-91. Epub 2000 Oct 17. PMID:11036083 doi:http://dx.doi.org/10.1074/jbc.M008159200
- ↑ Reid JL, Moqtaderi Z, Struhl K. Eaf3 regulates the global pattern of histone acetylation in Saccharomyces cerevisiae. Mol Cell Biol. 2004 Jan;24(2):757-64. PMID:14701747
- ↑ Kobor MS, Venkatasubrahmanyam S, Meneghini MD, Gin JW, Jennings JL, Link AJ, Madhani HD, Rine J. A protein complex containing the conserved Swi2/Snf2-related ATPase Swr1p deposits histone variant H2A.Z into euchromatin. PLoS Biol. 2004 May;2(5):E131. Epub 2004 Mar 23. PMID:15045029 doi:10.1371/journal.pbio.0020131
- ↑ Okuda M, Nishimura Y. The Eaf3 chromodomain acts as a pH sensor for gene expression by altering its binding affinity for histone methylated-lysine residues. Biosci Rep. 2020 Feb 28;40(2). pii: 222061. doi: 10.1042/BSR20191958. PMID:32031206 doi:http://dx.doi.org/10.1042/BSR20191958
