Oligomerization and Auto-methylation of the Human Lysine Methyltransferase SETD6

Lital Estrella Weil, Yulia Shmidov, Margarita Kublanovsky, David Morgenstern, Michal Feldman, Ronit Bitton, Dan Levy

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Signaling via lysine methylation by protein lysine methyltransferases (PKMTs), has been linked to diverse biological and disease processes. The mono-methyltransferase SETD6 (SET-domain-containing protein 6) is a member of the PKMT family and was previously shown to regulate essential cellular processes such as the NF-κB, WNT and the oxidative stress pathways. However, on the biochemical level, little is known about the enzymatic mode of action of SETD6. Here we provide evidence that SETD6 forms high-molecular-weight structures. Specifically, we demonstrate that SETD6 monomeric, dimeric and trimeric forms are stabilized by the methyl donor, S-adenosyl-L-methionine. We then show that SETD6 has auto-methylation activity at K39 and K179, which serves as the major auto-methylation sites with a moderate auto-methylation activity toward K372. A point mutation at K179 but not at K39 and K372, located at the SET domain of SETD6, impaired SETD6 ability to form a trimer, strongly implying a link between the auto-methylation and the oligomerization state. Finally, by radioactive in vitro methylation experiments and biochemical kinetics analysis, we show that the auto-methylation at K39 and K179 increases the catalytic rate of SETD6. Collectively, our data support a model by which SETD6 auto-methylation and self-interaction positively regulate its enzymatic activity in vitro and may suggest that other PKMTs are regulated in the same manner.

Original languageEnglish
Pages (from-to)4359-4368
Number of pages10
JournalJournal of Molecular Biology
Issue number21
StatePublished - 19 Oct 2018


  • SETD6
  • auto-methylation
  • lysine methylation

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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