Function of the MYND domain and C-terminal region in regulating the subcellular localization and catalytic activity of the SMYD family lysine methyltransferase Set5

Deepika Jaiswal, Rashi Turniansky, James J. Moresco, Sabeen Ikram, Ganesh Ramaprasad, Assefa Akinwole, Julie Wolf, John R. Yates, Erin M. Green

Research output: Contribution to journalArticle

Abstract

SMYD lysine methyltransferases target histones and nonhistone proteins for methylation and are critical regulators of muscle development and implicated in neoplastic transformation. They are characterized by a split catalytic SET domain and an intervening MYND zinc finger domain, as well as an extended C-terminal domain. Saccharomyces cerevisiae contains two SMYD proteins, Set5 and Set6, which share structural elements with the mammalian SMYD enzymes. Set5 is a histone H4 lysine 5, 8, and 12 methyltransferase, implicated in the regulation of stress responses and genome stability. While the SMYD proteins have diverse roles in cells, there are many gaps in our understanding of how these enzymes are regulated. Here, we performed mutational analysis of Set5, combined with phosphoproteomics, to identify regulatory mechanisms for its enzymatic activity and subcellular localization. Our results indicate that the MYND domain promotes Set5 chromatin association in cells and is required for its role in repressing subtelomeric genes. Phosphoproteomics revealed extensive phosphorylation of Set5, and phosphomimetic mutations enhance Set5 catalytic activity but diminish its ability to interact with chromatin in cells. These studies uncover multiple regions within Set5 that regulate its localization and activity and highlight potential avenues for understanding mechanisms controlling the diverse roles of SMYD enzymes.

Original languageEnglish (US)
Article numbere00341-19
JournalMolecular and cellular biology
Volume40
Issue number2
DOIs
StatePublished - Jan 1 2020
Externally publishedYes

Keywords

  • Chromatin
  • Histone methylation
  • Protein methylation
  • Protein phosphorylation
  • Yeast

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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