TY - JOUR
T1 - Oxidative misfolding of Cu/Zn-superoxide dismutase triggered by non-canonical intramolecular disulfide formation
AU - Anzai, Itsuki
AU - Tokuda, Eiichi
AU - Handa, Sumika
AU - Misawa, Hidemi
AU - Akiyama, Shuji
AU - Furukawa, Yoshiaki
N1 - Funding Information:
We thank Ms. Atsuko Shintani for performing Western blotting analysis on the mouse samples. This work was supported by Grants-in-Aid 16H04768 for Scientific Research (B) (to YF), 19H05765 for Scientific Research on Innovative Areas (to YF), and 18J12708 for JSPS Research Fellow (to IA) from the Ministry of Education, Culture, Sports, Science and Technology of Japan , Program for the Advancement of Research in Core Projects under Keio University’s Longevity Initiative , and also supportred in part by the Nanotechnology Platform Program (Molecule and Material Synthesis) and the Cooperative Research in Joint Studies at Institute for Molecular Science, Japan . Appendix A
Funding Information:
We thank Ms. Atsuko Shintani for performing Western blotting analysis on the mouse samples. This work was supported by Grants-in-Aid 16H04768 for Scientific Research (B) (to YF), 19H05765 for Scientific Research on Innovative Areas (to YF), and 18J12708 for JSPS Research Fellow (to IA) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Program for the Advancement of Research in Core Projects under Keio University's Longevity Initiative, and also supportred in part by the Nanotechnology Platform Program (Molecule and Material Synthesis) and the Cooperative Research in Joint Studies at Institute for Molecular Science, Japan.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - Misfolded Cu/Zn-superoxide dismutase (SOD1) is a pathological species in a subset of amyotrophic lateral sclerosis (ALS). Oxidative stress is known to increase in affected spinal cords of ALS and is thus considered to cause damages on SOD1 leading to the misfolding and aggregation. Despite this, it still remains elusive what triggers misfolding of SOD1 under oxidizing environment. Here, we show that a thiol group of Cys111 in SOD1 is oxidized to a sulfenic acid with hydrogen peroxide and reveal that further dissociation of the bound metal ions from the oxidized SOD1 allows another free Cys residue (Cys6) to nucleophilically attack the sulfenylated Cys111. As a result, an intra-molecular disulfide bond forms between Cys6 and Cys111. Such an abnormal SOD1 with the non-canonical disulfide bond was conformationally extended with significant cytotoxicity as well as high propensity to aggregate. Taken together, we propose a new model of SOD1 misfolding under oxidizing environment, in which formation of the non-canonical intramolecular disulfide bond plays a pivotal role.
AB - Misfolded Cu/Zn-superoxide dismutase (SOD1) is a pathological species in a subset of amyotrophic lateral sclerosis (ALS). Oxidative stress is known to increase in affected spinal cords of ALS and is thus considered to cause damages on SOD1 leading to the misfolding and aggregation. Despite this, it still remains elusive what triggers misfolding of SOD1 under oxidizing environment. Here, we show that a thiol group of Cys111 in SOD1 is oxidized to a sulfenic acid with hydrogen peroxide and reveal that further dissociation of the bound metal ions from the oxidized SOD1 allows another free Cys residue (Cys6) to nucleophilically attack the sulfenylated Cys111. As a result, an intra-molecular disulfide bond forms between Cys6 and Cys111. Such an abnormal SOD1 with the non-canonical disulfide bond was conformationally extended with significant cytotoxicity as well as high propensity to aggregate. Taken together, we propose a new model of SOD1 misfolding under oxidizing environment, in which formation of the non-canonical intramolecular disulfide bond plays a pivotal role.
KW - Disulfide formation
KW - Neurodegenerative diseases
KW - Protein misfolding
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U2 - 10.1016/j.freeradbiomed.2019.12.017
DO - 10.1016/j.freeradbiomed.2019.12.017
M3 - Article
C2 - 31863908
AN - SCOPUS:85076854806
VL - 147
SP - 187
EP - 199
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
ER -