Discovery of NSD2 non-histone substrates and design of a super-substrate.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
08 Jun 2024
08 Jun 2024
Historique:
received:
30
11
2023
accepted:
29
05
2024
medline:
9
6
2024
pubmed:
9
6
2024
entrez:
8
6
2024
Statut:
epublish
Résumé
The human protein lysine methyltransferase NSD2 catalyzes dimethylation at H3K36. It has very important roles in development and disease but many mechanistic features and its full spectrum of substrate proteins are unclear. Using peptide SPOT array methylation assays, we investigate the substrate sequence specificity of NSD2 and discover strong readout of residues between G33 (-3) and P38 (+2) on H3K36. Unexpectedly, we observe that amino acid residues different from natural ones in H3K36 are preferred at some positions. Combining four preferred residues led to the development of a super-substrate which is methylated much faster by NSD2 at peptide and protein level. Molecular dynamics simulations demonstrate that this activity increase is caused by distinct hyperactive conformations of the enzyme-peptide complex. To investigate the substrate spectrum of NSD2, we conducted a proteome wide search for nuclear proteins matching the specificity profile and discovered 22 peptide substrates of NSD2. In protein methylation studies, we identify K1033 of ATRX and K819 of FANCM as NSD2 methylation sites and also demonstrate their methylation in human cells. Both these proteins have important roles in DNA repair strengthening the connection of NSD2 and H3K36 methylation to DNA repair.
Identifiants
pubmed: 38851815
doi: 10.1038/s42003-024-06395-z
pii: 10.1038/s42003-024-06395-z
doi:
Substances chimiques
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
NSD2 protein, human
EC 2.1.1.43
Repressor Proteins
0
Histones
0
Peptides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
707Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : EXC 2075 390740016
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : EXC 2075 390740016
Informations de copyright
© 2024. The Author(s).
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