Key role of phosphorylation sites in ATPase domain and Linker region of MLH1 for DNA binding and functionality of MutLα.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
02 08 2023
02 08 2023
Historique:
received:
09
01
2023
accepted:
30
07
2023
medline:
4
8
2023
pubmed:
3
8
2023
entrez:
2
8
2023
Statut:
epublish
Résumé
MutLα is essential for human DNA mismatch repair (MMR). It harbors a latent endonuclease, is responsible for recruitment of process associated proteins and is relevant for strand discrimination. Recently, we demonstrated that the MMR function of MutLα is regulated by phosphorylation of MLH1 at serine (S) 477. In the current study, we focused on S87 located in the ATPase domain of MLH1 and on S446, S456 and S477 located in its linker region. We analysed the phosphorylation-dependent impact of these amino acids on DNA binding, MMR ability and thermal stability of MutLα. We were able to demonstrate that phosphorylation at S87 of MLH1 inhibits DNA binding of MutLα. In addition, we detected that its MMR function seems to be regulated predominantly via phosphorylation of serines in the linker domain, which are also partially involved in the regulation of DNA binding. Furthermore, we found that the thermal stability of MutLα decreased in relation to its phosphorylation status implying that complete phosphorylation might lead to instability and degradation of MLH1. In summary, we showed here, for the first time, a phosphorylation-dependent regulation of DNA binding of MutLα and hypothesized that this might significantly impact its functional regulation during MMR in vivo.
Identifiants
pubmed: 37532794
doi: 10.1038/s41598-023-39750-x
pii: 10.1038/s41598-023-39750-x
pmc: PMC10397344
doi:
Substances chimiques
Mismatch Repair Endonuclease PMS2
EC 3.6.1.3
MutL Protein Homolog 1
EC 3.6.1.3
DNA
9007-49-2
MLH1 protein, human
0
MutLalpha protein, human
0
MutL Proteins
EC 3.6.1.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12503Informations de copyright
© 2023. The Author(s).
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