@article{0790b6c5ae8c447488faa7b23b671f0c,
title = "CK2-mediated phosphorylation of SUZ12 promotes PRC2 function by stabilizing enzyme active site",
abstract = "Polycomb repressive complex 2 (PRC2) plays a key role in maintaining cell identity during differentiation. Methyltransferase activity of PRC2 on histone H3 lysine 27 is regulated by diverse cellular mechanisms, including posttranslational modification. Here, we report a unique phosphorylation-dependent mechanism stimulating PRC2 enzymatic activity. Residue S583 of SUZ12 is phosphorylated by casein kinase 2 (CK2) in cells. A crystal structure captures phosphorylation in action: the flexible phosphorylation-dependent stimulation loop harboring S583 becomes engaged with the catalytic SET domain through a phosphoserine-centered interaction network, stabilizing the enzyme active site and in particular S-adenosyl-methionine (SAM)-binding pocket. CK2-mediated S583 phosphorylation promotes catalysis by enhancing PRC2 binding to SAM and nucleosomal substrates and facilitates reporter gene repression. Loss of S583 phosphorylation impedes PRC2 recruitment and H3K27me3 deposition in pluripotent mESCs and compromises the ability of PRC2 to maintain differentiated cell identity.",
author = "Lihu Gong and Xiuli Liu and Lianying Jiao and Xin Yang and Andrew Lemoff and Xin Liu",
note = "Funding Information: The SUZ12 KO mESC line was a gift from Dr Kristian Helin from Institute of Cancer Research, London. The cDNAs of human PRC2 core components were kindly provided by Dr Robert E. Kingston. The authors acknowledge the UTSW Proteomics Core facility for assistance with the phosphopeptide LC-MS/MS experiments. This research was supported by Welch Foundation research grant I-1790 and NIH grants GM121662 and GM 136308 to Xin L. Xin L. is a W.W. Caruth, Jr, Scholar in Biomedical Research. This research also received support from the Cecil H. and Ida Green Center Training Program in Reproductive Biology Sciences Research. L.G. was supported by American Heart Association Postdoctoral Fellowship 19POST34450043. L.J. was supported by National Natural Science Foundation of China grant 32071213. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center (SBC) at the Advanced Photon Source. SBC-CAT is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. Funding Information: The SUZ12 KO mESC line was a gift from Dr Kristian Helin from Institute of Cancer Research, London. The cDNAs of human PRC2 core components were kindly provided by Dr Robert E. Kingston. The authors acknowledge the UTSW Proteomics Core facility for assistance with the phosphopeptide LC-MS/MS experiments. This research was supported by Welch Foundation research grant I-1790 and NIH grants GM121662 and GM 136308 to Xin L. Xin L. is a W.W. Caruth, Jr, Scholar in Biomedical Research. This research also received support from the Cecil H. and Ida Green Center Training Program in Reproductive Biology Sciences Research. L.G. was supported by American Heart Association Postdoctoral Fellowship 19POST34450043. L.J. was supported by National Natural Science Foundation of China grant 32071213. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center (SBC) at the Advanced Photon Source. SBC-CAT is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41467-022-34431-1",
language = "English (US)",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}