Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase γ: Novel Mechanisms of Function and Pathogenesis

Liliya Euro, Outi Haapanen, Tomasz Róg, Ilpo Vattulainen, Anu Suomalainen, Vivek Sharma

    Tutkimustuotos: ArtikkeliScientificvertaisarvioitu

    4 Sitaatiot (Scopus)

    Abstrakti

    DNA polymerase γ (Pol γ) is a key component of the mitochondrial DNA replisome and an important cause of neurological diseases. Despite the availability of its crystal structures, the molecular mechanism of DNA replication, the switch between polymerase and exonuclease activities, the site of replisomal interactions, and functional effects of patient mutations that do not affect direct catalysis have remained elusive. Here we report the first atomistic classical molecular dynamics simulations of the human Pol γ replicative complex. Our simulation data show that DNA binding triggers remarkable changes in the enzyme structure, including (1) completion of the DNA-binding channel via a dynamic subdomain, which in the apo form blocks the catalytic site, (2) stabilization of the structure through the distal accessory β-subunit, and (3) formation of a putative transient replisome-binding platform in the "intrinsic processivity" subdomain of the enzyme. Our data indicate that noncatalytic mutations may disrupt replisomal interactions, thereby causing Pol γ-associated neurodegenerative disorders.

    AlkuperäiskieliEnglanti
    Sivut1227-1238
    Sivumäärä12
    JulkaisuBiochemistry
    Vuosikerta56
    Numero9
    DOI - pysyväislinkit
    TilaJulkaistu - 7 maalisk. 2017
    OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

    Julkaisufoorumi-taso

    • Jufo-taso 1

    !!ASJC Scopus subject areas

    • Biochemistry

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