Abstract
Aggregation of protein molecules is a pathological hallmark of many neurodegenerative diseases. Abnormal modifications have often been observed in the aggregated proteins, supporting the aggregation mechanism regulated by post-translational modifications on proteins. Modifications are in general assumed to occur in soluble proteins before aggregation, but actually it remains quite obscure when proteins are modified in the course of the aggregation. Here we focus upon aggregation of huntingtin (HTT), which causes a neurodegenerative disorder, Huntington disease, and we show that oxidation of a methionine residue in HTT occurs in vitro and also in vivo. Copper ions as well as added hydrogen peroxide are found to oxidize the methionine residue, but notably, this oxidative modification occurs only in the aggregated HTT but not in the soluble state. Furthermore, the methionine oxidation creates additional interactions among HTT aggregates and alters overall morphologies of the aggregates. We thus reveal that protein aggregates can be a target of oxidative modifications and propose that such a "post-aggregation" modification is a relevant factor to regulate properties of protein aggregates.
| Original language | English |
|---|---|
| Pages (from-to) | 34764-34775 |
| Number of pages | 12 |
| Journal | Journal of Biological Chemistry |
| Volume | 287 |
| Issue number | 41 |
| DOIs | |
| Publication status | Published - 2012 Oct 5 |
Fingerprint
ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
Cite this
Post-aggregation oxidation of mutant huntingtin controls the interactions between aggregates. / Mitomi, Yasushi; Nomura, Takao; Kurosawa, Masaru; Nukina, Nobuyuki; Furukawa, Yoshiaki.
In: Journal of Biological Chemistry, Vol. 287, No. 41, 05.10.2012, p. 34764-34775.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Post-aggregation oxidation of mutant huntingtin controls the interactions between aggregates
AU - Mitomi, Yasushi
AU - Nomura, Takao
AU - Kurosawa, Masaru
AU - Nukina, Nobuyuki
AU - Furukawa, Yoshiaki
PY - 2012/10/5
Y1 - 2012/10/5
N2 - Aggregation of protein molecules is a pathological hallmark of many neurodegenerative diseases. Abnormal modifications have often been observed in the aggregated proteins, supporting the aggregation mechanism regulated by post-translational modifications on proteins. Modifications are in general assumed to occur in soluble proteins before aggregation, but actually it remains quite obscure when proteins are modified in the course of the aggregation. Here we focus upon aggregation of huntingtin (HTT), which causes a neurodegenerative disorder, Huntington disease, and we show that oxidation of a methionine residue in HTT occurs in vitro and also in vivo. Copper ions as well as added hydrogen peroxide are found to oxidize the methionine residue, but notably, this oxidative modification occurs only in the aggregated HTT but not in the soluble state. Furthermore, the methionine oxidation creates additional interactions among HTT aggregates and alters overall morphologies of the aggregates. We thus reveal that protein aggregates can be a target of oxidative modifications and propose that such a "post-aggregation" modification is a relevant factor to regulate properties of protein aggregates.
AB - Aggregation of protein molecules is a pathological hallmark of many neurodegenerative diseases. Abnormal modifications have often been observed in the aggregated proteins, supporting the aggregation mechanism regulated by post-translational modifications on proteins. Modifications are in general assumed to occur in soluble proteins before aggregation, but actually it remains quite obscure when proteins are modified in the course of the aggregation. Here we focus upon aggregation of huntingtin (HTT), which causes a neurodegenerative disorder, Huntington disease, and we show that oxidation of a methionine residue in HTT occurs in vitro and also in vivo. Copper ions as well as added hydrogen peroxide are found to oxidize the methionine residue, but notably, this oxidative modification occurs only in the aggregated HTT but not in the soluble state. Furthermore, the methionine oxidation creates additional interactions among HTT aggregates and alters overall morphologies of the aggregates. We thus reveal that protein aggregates can be a target of oxidative modifications and propose that such a "post-aggregation" modification is a relevant factor to regulate properties of protein aggregates.
UR - http://www.scopus.com/inward/record.url?scp=84867267823&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867267823&partnerID=8YFLogxK
U2 - 10.1074/jbc.M112.387035
DO - 10.1074/jbc.M112.387035
M3 - Article
C2 - 22891249
AN - SCOPUS:84867267823
VL - 287
SP - 34764
EP - 34775
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 41
ER -