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

Jean François Couture, Evys Collazo, Joseph S. Brunzelle, Raymond C. Trievel*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    175 Scopus citations

    Abstract

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

    Original languageEnglish (US)
    Pages (from-to)1455-1465
    Number of pages11
    JournalGenes and Development
    Volume19
    Issue number12
    DOIs
    StatePublished - Jun 15 2005

    Keywords

    • Histone modifications
    • Mitosis
    • Protein lysine methylation
    • SET domain
    • Substrate specificity
    • Transcription

    ASJC Scopus subject areas

    • Genetics
    • Developmental Biology

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