Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA polymerase ß activity.
J Mol Graph Model
; 84: 236-241, 2018 09.
Article
em En
| MEDLINE
| ID: mdl-30138833
ABSTRACT
DNA polymerase ß is a 39â¯kDa enzyme that is a major component of Base Excision Repair in human cells. The enzyme comprises two major domains, a 31â¯kDa domain responsible for the polymerase activity and an 8â¯kDa domain, which bind ssDNA and has a deoxyribose phosphate (dRP) lyase activity. DNA polymerase ß was shown to be phosphorylated in vitro with protein kinase C (PKC) at serines 44 and 55 (S44 and S55), resulting in loss of its polymerase enzymic activity, but not its ability to bind ssDNA. In this study, we investigate the potential phosphorylation-induced structural changes for DNA polymerase ß using molecular dynamics simulations. The simulations show drastic conformational changes of the polymerase structure as a result of S44 phosphorylation. Phosphorylation-induced conformational changes transform the closed (active) enzyme structure into an open one. Further analysis of the results points to a key hydrogen bond and newly formed salt bridges as potential drivers of these structural fluctuations. The changes observed with S55/44 and S55 phosphorylation were less dramatic and the integrity of the H-bond was not compromised. Thus the phosphorylation of S44 is the major contributor to structural fluctuations that lead to loss of enzymatic activity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Serina
/
DNA Polimerase beta
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Eletricidade Estática
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Simulação de Dinâmica Molecular
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article