Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase

• DOI: 10.1101/gad.1318405
• Publication Date: 2005-06-03T00:34:31Z
• Authors: Jean-François Cou...; Evys Collazo; Joseph S. Brunzelle; Raymond C. Trievel
• Keywords: Histone H4; Histone code; Histone Methylation

SET8 (also known as PR-SET7) is a histone H4-Lys-20-specific methyltransferase that implicated in cell-cycle-dependent transcriptional silencing and mitotic regulation metazoans. Herein we report the crystal structure of human (hSET8) bound to H4 peptide bearing Lys-20 product cofactor S-adenosylhomocysteine. Histone intercalates substrate-binding cleft an extended parallel β-strand. Residues preceding engage extensive array salt bridge, hydrogen bond, van der Waals interactions with hSET8, while C-terminal residues bind through predominantly hydrophobic interactions. Mutational analysis both reveals N C termini are critical for conferring substrate specificity. Finally, specificity indicates hSET8 monomethylase, consistent its role maintenance monomethylation during cell division.