The structure of NSD1 reveals an autoregulatory mechanism underlying histone H3K36 methylation

J Biol Chem. 2011 Mar 11;286(10):8361-8368. doi: 10.1074/jbc.M110.204115. Epub 2010 Dec 31.

Abstract

The Sotos syndrome gene product, NSD1, is a SET domain histone methyltransferase that primarily dimethylates nucleosomal histone H3 lysine 36 (H3K36). To date, the intrinsic properties of NSD1 that determine its nucleosomal substrate selectivity and dimethyl H3K36 product specificity remain unknown. The 1.7 Å structure of the catalytic domain of NSD1 presented here shows that a regulatory loop adopts a conformation that prevents free access of H3K36 to the bound S-adenosyl-L-methionine. Molecular dynamics simulation and computational docking revealed that this normally inhibitory loop can adopt an active conformation, allowing H3K36 access to the active site, and that the nucleosome may stabilize the active conformation of the regulatory loop. Hence, our study reveals an autoregulatory mechanism of NSD1 and provides insight into the molecular mechanism of the nucleosomal substrate selectivity of this disease-related H3K36 methyltransferase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation*
  • Crystallography, X-Ray
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / chemistry*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / chemistry*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Methylation
  • Models, Molecular*
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Sotos Syndrome / genetics
  • Sotos Syndrome / metabolism
  • Structure-Activity Relationship

Substances

  • Histones
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • NSD1 protein, human

Associated data

  • PDB/3OOI