دورية أكاديمية
Convergent evolution of chromatin modification by structurally distinct enzymes: comparative enzymology of histone H3 Lys²⁷ methylation by human polycomb repressive complex 2 and vSET.
| العنوان: | Convergent evolution of chromatin modification by structurally distinct enzymes: comparative enzymology of histone H3 Lys²⁷ methylation by human polycomb repressive complex 2 and vSET. |
|---|---|
| المؤلفون: | Swalm BM; Epizyme Inc., 400 Technology Square, Cambridge, MA 02139, USA., Hallenbeck KK, Majer CR, Jin L, Scott MP, Moyer MP, Copeland RA, Wigle TJ |
| المصدر: | The Biochemical journal [Biochem J] 2013 Jul 15; Vol. 453 (2), pp. 241-7. |
| نوع المنشور: | Comparative Study; Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Published by Portland Press on behalf of the Biochemical Society Country of Publication: England NLM ID: 2984726R Publication Model: Print Cited Medium: Internet ISSN: 1470-8728 (Electronic) Linking ISSN: 02646021 NLM ISO Abbreviation: Biochem J Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: London, UK : Published by Portland Press on behalf of the Biochemical Society |
| مواضيع طبية MeSH: | Chromatin/*metabolism , Histones/*metabolism , Lysine/*metabolism , Polycomb Repressive Complex 2/*metabolism, Amino Acid Sequence ; Biocatalysis ; Humans ; Methylation ; Methyltransferases/chemistry ; Methyltransferases/metabolism ; Molecular Sequence Data ; Polycomb Repressive Complex 2/chemistry ; Protein Conformation ; Sequence Homology, Amino Acid |
| مستخلص: | H3K27 (histone H3 Lys27) methylation is an important epigenetic modification that regulates gene transcription. In humans, EZH (enhancer of zeste homologue) 1 and EZH2 are the only enzymes capable of catalysing methylation of H3K27. There is great interest in understanding structure-function relationships for EZH2, as genetic alterations in this enzyme are thought to play a causal role in a number of human cancers. EZH2 is challenging to study because it is only active in the context of the multi-subunit PRC2 (polycomb repressive complex 2). vSET is a viral lysine methyltransferase that represents the smallest protein unit capable of catalysing H3K27 methylation. The crystal structure of this minimal catalytic protein has been solved and researchers have suggested that vSET might prove useful as an EZH2 surrogate for the development of active site-directed inhibitors. To test this proposition, we conducted comparative enzymatic analysis of human EZH2 and vSET and report that, although both enzymes share similar preferences for methylation of H3K27, they diverge in terms of their permissiveness for catalysing methylation of alternative histone lysine sites, their relative preferences for utilization of multimeric macromolecular substrates, their active site primary sequences and, most importantly, their sensitivity to inhibition by drug-like small molecules. The cumulative data led us to suggest that EZH2 and vSET have very distinct active site structures, despite the commonality of the reaction catalysed by the two enzymes. Hence, the EZH2 and vSET pair of enzymes represent an example of convergent evolution in which distinct structural solutions have developed to solve a common catalytic need. |
| المشرفين على المادة: | 0 (Chromatin) 0 (Histones) EC 2.1.1.- (Methyltransferases) EC 2.1.1.43 (Polycomb Repressive Complex 2) K3Z4F929H6 (Lysine) |
| تواريخ الأحداث: | Date Created: 20130518 Date Completed: 20130916 Latest Revision: 20131121 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1042/BJ20130439 |
| PMID: | 23679895 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1470-8728 |
|---|---|
| DOI: | 10.1042/BJ20130439 |