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Chem Biol. 2014 Feb 20;21(2):226-37. doi: 10.1016/j.chembiol.2013.10.016. Epub 2014 Jan 9.

Substrate specificity analysis and novel substrates of the protein lysine methyltransferase NSD1.

Author information

1
Institute of Biochemistry, Stuttgart University, Pfaffenwaldring 55, Stuttgart D-70569, Germany.
2
Biochemistry Laboratory, School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, Bremen 28759, Germany.
3
Institute for Biochemistry and Molecular Cell Biology, University of Göttingen, Humboldtallee 23, Göttingen D-37073, Germany.
4
Institute of Biochemistry, Stuttgart University, Pfaffenwaldring 55, Stuttgart D-70569, Germany. Electronic address: albert.jeltsch@ibc.uni-stuttgart.de.

Abstract

The nuclear receptor binding SET [su(var) 3-9, enhancer of zeste, trithorax] domain-containing protein 1 (NSD1) protein lysine methyltransferase (PKMT) was known to methylate histone H3 lysine 36 (H3K36). We show here that NSD1 prefers aromatic, hydrophobic, and basic residues at the -2, -1 and +2, and +1 sites of its substrate peptide, respectively. We show methylation of 25 nonhistone peptide substrates by NSD1, two of which were (weakly) methylated at the protein level, suggesting that unstructured protein regions are preferred NSD1 substrates. Methylation of H4K20 and p65 was not observed. We discovered strong methylation of H1.5 K168, which represents the best NSD1 substrate protein identified so far, and methylation of H4K44 which was weaker than H3K36. Furthermore, we show that Sotos mutations in the SET domain of NSD1 inactivate the enzyme. Our results illustrate the importance of specificity analyses of PKMTs for understanding protein lysine methylation signaling pathways.

PMID:
24412544
DOI:
10.1016/j.chembiol.2013.10.016
[Indexed for MEDLINE]
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