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

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftBiochemistry
Vol/bind56
Udgave nummer9
Sider (fra-til)1227-1238
ISSN0006-2960
DOI
StatusUdgivet - 2017

Fingeraftryk

DNA-Directed DNA Polymerase
Molecular Dynamics Simulation
Mitochondrial DNA
Molecular dynamics
Exonucleases
Mutation
DNA
Computer simulation
Enzymes
Neurodegenerative Diseases
Catalytic Domain
Accessories
Catalysis
Stabilization
Crystal structure
Switches
Availability

Citer dette

Euro, Liliya ; Haapanen, Outi ; Róg, Tomasz ; Vattulainen, Ilpo ; Suomalainen, Anu ; Sharma, Vivek. / Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase γ : Novel Mechanisms of Function and Pathogenesis. I: Biochemistry. 2017 ; Bind 56, Nr. 9. s. 1227-1238.
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abstract = "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.",
author = "Liliya Euro and Outi Haapanen and Tomasz R{\'o}g and Ilpo Vattulainen and Anu Suomalainen and Vivek Sharma",
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doi = "10.1021/acs.biochem.6b00934",
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Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase γ : Novel Mechanisms of Function and Pathogenesis. / Euro, Liliya; Haapanen, Outi; Róg, Tomasz; Vattulainen, Ilpo; Suomalainen, Anu; Sharma, Vivek.

I: Biochemistry, Bind 56, Nr. 9, 2017, s. 1227-1238.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase γ

T2 - Novel Mechanisms of Function and Pathogenesis

AU - Euro, Liliya

AU - Haapanen, Outi

AU - Róg, Tomasz

AU - Vattulainen, Ilpo

AU - Suomalainen, Anu

AU - Sharma, Vivek

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.1021/acs.biochem.6b00934

DO - 10.1021/acs.biochem.6b00934

M3 - Journal article

C2 - 28206745

AN - SCOPUS:85014731062

VL - 56

SP - 1227

EP - 1238

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 9

ER -