crystal structures of histone and p53 methyltransferase smyd2 reveal a conformational flexibility of the autoinhibitory c-terminal domain组蛋白的晶体结构和p53甲基转移酶smyd2揭示了构象的灵活性autoinhibitory c端域.pdfVIP

Crystal Structures of Histone and p53 Methyltransferase SmyD2 Reveal a Conformational Flexibility of the Autoinhibitory C-Terminal Domain 1 1 2 1 Yuanyuan Jiang , Nualpun Sirinupong , Joseph Brunzelle , Zhe Yang * 1 Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, United States of America, 2 Advance Photon Source, Argonne National Lab, Argonne, Illinois, United States of America Abstract SmyD2 belongs to a new class of chromatin regulators that control gene expression in heart development and tumorigenesis. Besides methylation of histone H3 K4, SmyD2 can methylate non-histone targets including p53 and the retinoblastoma tumor suppressor. The methyltransferase activity of SmyD proteins has been proposed to be regulated by autoinhibition via the intra- and interdomain bending of the conserved C-terminal domain (CTD). However, there has been no direct evidence of a conformational change in the CTD. Here, we report two crystal structures of SmyD2 bound either to the cofactor product S-adenosylhomocysteine or to the inhibitor sinefungin. SmyD2 has a two-lobed structure with the active site located at the bottom of a deep crevice formed between the CTD and the catalytic domain. By extensive engagement with the methyltransferase domain, the CTD stabilizes the autoinhibited conformation of SmyD2 and restricts access to the catalytic site. Unexpectedly, despite that the two SmyD2 structures are highly superimposable, significant differences are observed in the first two helices of the CTDs: the two helices bend outwards and move away from the catalytic domain to