CK2-mediated phosphorylation of SUZ12 promotes PRC2 function by stabilizing enzyme active site

Lihu Gong, Xiuli Liu, Lianying Jiao, Xin Yang, Andrew Lemoff and Xin Liu ()
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Lihu Gong: University of Texas Southwestern Medical Center
Xiuli Liu: University of Texas Southwestern Medical Center
Lianying Jiao: University of Texas Southwestern Medical Center
Xin Yang: University of Texas Southwestern Medical Center
Andrew Lemoff: University of Texas Southwestern Medical Center
Xin Liu: University of Texas Southwestern Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34431-1

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