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Structural basis of SETD6-mediated regulation of the NF-kB network via methyl-lysine signaling

Yanqi Chang1, Dan Levy, John R Horton

  • 1Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, USA.

Nucleic Acids Research
|April 26, 2011
PubMed

Insights

SET domain containing 6 (SETD6) modifies RelA, a subunit of nuclear factor kappa B (NF-κB). This methylation and phosphorylation switch regulates NF-κB signaling, with structural insights into SETD6 and GLP interactions.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Biochemistry

Background:

  • Nuclear factor kappa B (NF-κB) signaling is crucial in cellular responses.
  • RelA, a key NF-κB subunit, undergoes post-translational modifications like methylation and phosphorylation.
  • SET domain containing 6 (SETD6) and G9a-like protein (GLP) are involved in RelA modification.

Purpose of the Study:

  • To elucidate the structural basis of RelA Lys310 methylation by SETD6.
  • To understand how GLP recognizes methylated RelA.
  • To investigate the inhibitory mechanism of Ser311 phosphorylation on Lys310 methylation and GLP binding.

Main Methods:

  • X-ray crystallography of SETD6 complexed with a RelA peptide.
  • Structural modeling of GLP ankyrin repeats with a methylated RelA peptide.
  • Bioinformatic analysis of SETD6 structural similarity.

Main Results:

  • The structure of SETD6 reveals a V-like protein fold and suggests a binding model for NF-κB.
  • Structural modeling explains how Ser311 phosphorylation inhibits Lys310 methylation and GLP binding.
  • SETD6 shares evolutionary conservation with Rubisco methyltransferases.

Conclusions:

  • A structural mechanism for the methylation-phosphorylation switch at RelA Lys310/Ser311 is proposed.
  • SETD6 and GLP play critical roles in regulating NF-κB signaling through RelA modification.
  • The evolutionary conservation of SETD6 highlights the importance of this regulatory pathway.

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