Crystal structure of cardiac-specific histone methyltransferase SmyD1 reveals unusual active site architecture

Nualpun Sirinupong, Joseph Brunzelle, Jun Ye, Ali Pirzada, Lindsey Nico, Zhe Yang*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    55 Scopus citations

    Abstract

    SmyD1 is a cardiac- and muscle-specific histone methyltransferase that methylates histone H3 at lysine 4 and regulates gene transcription in early heart development. The unique domain structure characterized by a "split" SET domain, a conserved MYND zinc finger, and a novel C-terminal domain (CTD) distinguishes SmyD1 from other SET domain containing methyltransferases. Here we report the crystal structure of full-length SmyD1 in complex with the cofactor analog sinefungin at 2.3 Å. The structure reveals that SmyD1 folds into a wrench-shaped structure with two thick "grips" separated by a large, deep concave opening. Importantly, our structural and functional analysis suggests that SmyD1 appears to be regulated by an autoinhibition mechanism, and that unusually spacious target lysine-access channel and the presence of the CTD domain both negatively contribute to the regulation of this cardiovascularly relevant methyltransferase. Furthermore, our structure also provides a structural basis for the interaction between SmyD1 and cardiac transcription factor skNAC, and suggests that the MYND domain may primarily serve as a protein interaction module and cooperate SmyD1 with skNAC to regulate cardiomyocyte growth and maturation. Overall, our data provide novel insights into the mechanism of SmyD1 regulation, which would be helpful in further understanding the role of this protein in heart development and cardiovascular diseases.

    Original languageEnglish (US)
    Pages (from-to)40635-40644
    Number of pages10
    JournalJournal of Biological Chemistry
    Volume285
    Issue number52
    DOIs
    StatePublished - Dec 24 2010

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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