Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease

R. Kiss, Max Zhu, Balázs Jójárt, András Czajlik, Katalin Solti, Balázs Fórizs, Éva Nagy, F. Zsila, Tamás Beke-Somfai, Gergely Tóth

Research output: Article

10 Citations (Scopus)

Abstract

DJ-1 (PARK7) is a multifunctional protein linked to the onset and progression of a number of diseases, most of which are associated with high oxidative stress. The Cys106 of DJ-1 is unusually reactive and thus sensitive to oxidation, and due to high oxidative stress it was observed to be in various oxidized states in disease condition. The oxidation state of Cys106 of DJ-1 is believed to determine the specific functions of the protein in normal and disease conditions. Here we report molecular dynamics simulation and biophysical experimental studies on DJ-1 in reduced (Cys106, –S), oxidized (Cys106, –SO2 ), and over-oxidized (Cys106, –SO3 ) states. To simulate the different oxidation states of Cys106 in DJ-1, AMBER related force field parameters were developed and reported for 3-sulfinoalanine and cysteine sulfonic acid. Our studies found that the overall structure of DJ-1 in different oxidation states was similar globally, while it differed locally significantly, which have implications on its stability, function and its link to disease on-set. Importantly, the results suggest that over-oxidation may trigger loss of functions due to local structural modification in the Cys106 containing pocket of DJ-1 and structurally destabilize the dimeric state of DJ-1, which is believed to be its bioactive conformation. Such loss of functions would result in reduced ability of DJ-1 to protect from oxidative stress insults and may lead to increased progression of disease.

Original languageEnglish
Pages (from-to)2619-2629
Number of pages11
JournalBiochimica et Biophysica Acta - General Subjects
Volume1861
Issue number11
DOIs
Publication statusPublished - nov. 1 2017

Fingerprint

Oxidative stress
Oxidation
Oxidative Stress
Sulfonic Acids
Molecular Dynamics Simulation
Cysteine
Disease Progression
Proteins
Conformations
Molecular dynamics
Computer simulation

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease. / Kiss, R.; Zhu, Max; Jójárt, Balázs; Czajlik, András; Solti, Katalin; Fórizs, Balázs; Nagy, Éva; Zsila, F.; Beke-Somfai, Tamás; Tóth, Gergely.

In: Biochimica et Biophysica Acta - General Subjects, Vol. 1861, No. 11, 01.11.2017, p. 2619-2629.

Research output: Article

Kiss, R. ; Zhu, Max ; Jójárt, Balázs ; Czajlik, András ; Solti, Katalin ; Fórizs, Balázs ; Nagy, Éva ; Zsila, F. ; Beke-Somfai, Tamás ; Tóth, Gergely. / Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease. In: Biochimica et Biophysica Acta - General Subjects. 2017 ; Vol. 1861, No. 11. pp. 2619-2629.
@article{27dc6f4fe5114fa5af47a873be568a79,
title = "Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease",
abstract = "DJ-1 (PARK7) is a multifunctional protein linked to the onset and progression of a number of diseases, most of which are associated with high oxidative stress. The Cys106 of DJ-1 is unusually reactive and thus sensitive to oxidation, and due to high oxidative stress it was observed to be in various oxidized states in disease condition. The oxidation state of Cys106 of DJ-1 is believed to determine the specific functions of the protein in normal and disease conditions. Here we report molecular dynamics simulation and biophysical experimental studies on DJ-1 in reduced (Cys106, –S−), oxidized (Cys106, –SO2 −), and over-oxidized (Cys106, –SO3 −) states. To simulate the different oxidation states of Cys106 in DJ-1, AMBER related force field parameters were developed and reported for 3-sulfinoalanine and cysteine sulfonic acid. Our studies found that the overall structure of DJ-1 in different oxidation states was similar globally, while it differed locally significantly, which have implications on its stability, function and its link to disease on-set. Importantly, the results suggest that over-oxidation may trigger loss of functions due to local structural modification in the Cys106 containing pocket of DJ-1 and structurally destabilize the dimeric state of DJ-1, which is believed to be its bioactive conformation. Such loss of functions would result in reduced ability of DJ-1 to protect from oxidative stress insults and may lead to increased progression of disease.",
keywords = "DJ-1, Molecular dynamics, Oxidative stress, Parkinson's disease, Protein structure, Structure based drug design",
author = "R. Kiss and Max Zhu and Bal{\'a}zs J{\'o}j{\'a}rt and Andr{\'a}s Czajlik and Katalin Solti and Bal{\'a}zs F{\'o}rizs and {\'E}va Nagy and F. Zsila and Tam{\'a}s Beke-Somfai and Gergely T{\'o}th",
year = "2017",
month = "11",
day = "1",
doi = "10.1016/j.bbagen.2017.08.017",
language = "English",
volume = "1861",
pages = "2619--2629",
journal = "Biochimica et Biophysica Acta - General Subjects",
issn = "0304-4165",
publisher = "Elsevier",
number = "11",

}

TY - JOUR

T1 - Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease

AU - Kiss, R.

AU - Zhu, Max

AU - Jójárt, Balázs

AU - Czajlik, András

AU - Solti, Katalin

AU - Fórizs, Balázs

AU - Nagy, Éva

AU - Zsila, F.

AU - Beke-Somfai, Tamás

AU - Tóth, Gergely

PY - 2017/11/1

Y1 - 2017/11/1

N2 - DJ-1 (PARK7) is a multifunctional protein linked to the onset and progression of a number of diseases, most of which are associated with high oxidative stress. The Cys106 of DJ-1 is unusually reactive and thus sensitive to oxidation, and due to high oxidative stress it was observed to be in various oxidized states in disease condition. The oxidation state of Cys106 of DJ-1 is believed to determine the specific functions of the protein in normal and disease conditions. Here we report molecular dynamics simulation and biophysical experimental studies on DJ-1 in reduced (Cys106, –S−), oxidized (Cys106, –SO2 −), and over-oxidized (Cys106, –SO3 −) states. To simulate the different oxidation states of Cys106 in DJ-1, AMBER related force field parameters were developed and reported for 3-sulfinoalanine and cysteine sulfonic acid. Our studies found that the overall structure of DJ-1 in different oxidation states was similar globally, while it differed locally significantly, which have implications on its stability, function and its link to disease on-set. Importantly, the results suggest that over-oxidation may trigger loss of functions due to local structural modification in the Cys106 containing pocket of DJ-1 and structurally destabilize the dimeric state of DJ-1, which is believed to be its bioactive conformation. Such loss of functions would result in reduced ability of DJ-1 to protect from oxidative stress insults and may lead to increased progression of disease.

AB - DJ-1 (PARK7) is a multifunctional protein linked to the onset and progression of a number of diseases, most of which are associated with high oxidative stress. The Cys106 of DJ-1 is unusually reactive and thus sensitive to oxidation, and due to high oxidative stress it was observed to be in various oxidized states in disease condition. The oxidation state of Cys106 of DJ-1 is believed to determine the specific functions of the protein in normal and disease conditions. Here we report molecular dynamics simulation and biophysical experimental studies on DJ-1 in reduced (Cys106, –S−), oxidized (Cys106, –SO2 −), and over-oxidized (Cys106, –SO3 −) states. To simulate the different oxidation states of Cys106 in DJ-1, AMBER related force field parameters were developed and reported for 3-sulfinoalanine and cysteine sulfonic acid. Our studies found that the overall structure of DJ-1 in different oxidation states was similar globally, while it differed locally significantly, which have implications on its stability, function and its link to disease on-set. Importantly, the results suggest that over-oxidation may trigger loss of functions due to local structural modification in the Cys106 containing pocket of DJ-1 and structurally destabilize the dimeric state of DJ-1, which is believed to be its bioactive conformation. Such loss of functions would result in reduced ability of DJ-1 to protect from oxidative stress insults and may lead to increased progression of disease.

KW - DJ-1

KW - Molecular dynamics

KW - Oxidative stress

KW - Parkinson's disease

KW - Protein structure

KW - Structure based drug design

UR - http://www.scopus.com/inward/record.url?scp=85029596045&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029596045&partnerID=8YFLogxK

U2 - 10.1016/j.bbagen.2017.08.017

DO - 10.1016/j.bbagen.2017.08.017

M3 - Article

C2 - 28844983

AN - SCOPUS:85029596045

VL - 1861

SP - 2619

EP - 2629

JO - Biochimica et Biophysica Acta - General Subjects

JF - Biochimica et Biophysica Acta - General Subjects

SN - 0304-4165

IS - 11

ER -