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

• Published in: Nature communications 2022-11, Vol.13 (1), p.6781-6781, Article 6781
• Main Authors: Gong, Lihu, Liu, Xiuli, Jiao, Lianying, Yang, Xin, Lemoff, Andrew, Liu, Xin
• Format: Article
• Language: English
• Subjects: 13/100; 38/109; 38/15; 631/337/176/2016; 631/45/173; 631/532/2117; 631/535/1266; 631/92/458/1733; 82/16; 82/29; 82/58; 82/80; 82/83; Binding; Casein; Casein kinase II; Casein Kinase II - metabolism; Catalysis; Catalytic Domain; Cell differentiation; Crystal structure; Differentiation (biology); Enzymatic activity; Enzymes; Histone H3; Histones; Histones - metabolism; Humanities and Social Sciences; Kinases; Lysine; Methionine; Methyltransferase; multidisciplinary; Phosphorylation; Phosphoserine; Pluripotency; Polycomb group proteins; Polycomb Repressive Complex 2 - metabolism; Reporter gene; Science; Science (multidisciplinary); Stem cells; Substrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34431-1

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. Here the authors identify SUZ12 as a cellular substate of casein kinase 2 (CK2), and show this phosphorylation changes the active site structure of Polycomb repressive complex 2 (PRC2) and promotes PRC2 function in cell identity maintenance during stem cell differentiation.