@article{a695007342a241f9a264fb7d8a59631a,
title = "A complete methyl-lysine binding aromatic cage constructed by two domains of PHF2",
abstract = "The N-terminal half of PHF2 harbors both a plant homeodomain (PHD) and a Jumonji domain. The PHD recognizes both histone H3 trimethylated at lysine 4 and methylated nonhistone proteins including vaccinia-related kinase 1 (VRK1). The Jumonji domain erases the repressive dimethylation mark from histone H3 lysine 9 (H3K9me2) at select promoters. The N-terminal amino acid sequences of H3 (AR2TK4) and VRK1 (PR2VK4) bear an arginine at position 2 and lysine at position 4. Here, we show that the PHF2 N-terminal half binds to H3 and VRK1 peptides containing K4me3, with dissociation constants (KD values) of 160 nM and 42 nM, respectively, which are 4 × and 21 × lower (and higher affinities) than for the isolated PHD domain of PHF2. X-ray crystallography revealed that the K4me3-containing peptide is positioned within the PHD and Jumonji interface, with the positively charged R2 residue engaging acidic residues of the PHD and Jumonji domains and with the K4me3 moiety encircled by aromatic residues from both domains. We suggest that the micromolar binding affinities commonly observed for isolated methyl-lysine reader domains could be improved via additional functional interactions within the same polypeptide or its binding partners.",
keywords = "aromatic cage, histone H3 lysine 4 tri-methylation, Jumonji domain, Methyl-lysine binding, plant homeodomain, plant homeodomain finger 2",
author = "Horton, {John R.} and Jujun Zhou and Qin Chen and Xing Zhang and Bedford, {Mark T.} and Xiaodong Cheng",
note = "Funding Information: The work was supported by the US National Institutes of Health ( R35GM134744 to X. C.) and the Cancer Prevention and Research Institute of Texas ( RR160029 to X. C.). M. T. B. is supported by NIH GM126421 and CPRIT RP180804 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: We thank Dr Briana Dennehey for editing the article and her insightful comments. We thank the beamline scientists of the Southeast Regional Collaborative Access Team (SER-CAT) at the Advanced Photon Source (APS), Argonne National Laboratory, USA. The use of SER-CAT is supported by its member institutions and equipment grants ( S10_RR25528 , S10_RR028976 , and S10_OD027000 ) from the US National Institutes of Health . Use of the APS was supported by the U.S. Department of Energy , Office of Science , Office of Basic Energy Sciences , under contract W-31-109-Eng-38 . Funding Information: We thank Dr Briana Dennehey for editing the article and her insightful comments. We thank the beamline scientists of the Southeast Regional Collaborative Access Team (SER-CAT) at the Advanced Photon Source (APS), Argonne National Laboratory, USA. The use of SER-CAT is supported by its member institutions and equipment grants (S10_RR25528, S10_RR028976, and S10_OD027000) from the US National Institutes of Health. Use of the APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract W-31-109-Eng-38. J. R. H. J. Z. Q. C. and M. T. B. investigation; X. Z. supervision; X. Z. M. T. B. and X. C. conceptualization; X. Z. project administration; X. C. funding acquisition; X. C. writing–original draft; X. C. and M. T. B. writing–review and editing; X. C. methodology. The work was supported by the US National Institutes of Health (R35GM134744 to X. C.) and the Cancer Prevention and Research Institute of Texas (RR160029 to X. C.). M. T. B. is supported by NIH GM126421 and CPRIT RP180804. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2023",
month = feb,
doi = "10.1016/j.jbc.2022.102862",
language = "English (US)",
volume = "299",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "2",
}