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Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA Polymerase β’s activity

Homouz, D. and Tan, K. H. Joyce and Shamsir, M. Shahir and Moustafa, I. M. and Idriss, H. T. (2018) Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA Polymerase β’s activity. Journal of Molecular Graphics and Modelling, 84 . pp. 236-241. ISSN 1093-3263

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Official URL: http://dx.doi.org/10.1016/j.jmgm.2018.08.007

Abstract

DNA polymerase ß is a 39 kDa enzyme that is a major component of Base Excision Repair in human cells. The enzyme comprises two major domains, a 31 kDa domain responsible for the polymerase activity and an 8 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.

Item Type:Article
Uncontrolled Keywords:DNA, enzyme activity, hydrogen bonds
Subjects:Q Science > Q Science (General)
Divisions:Biosciences and Medical Engineering
ID Code:81810
Deposited By: Narimah Nawil
Deposited On:29 Sep 2019 16:13
Last Modified:29 Sep 2019 16:13

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