Post-aggregation oxidation of mutant huntingtin controls the interactions between aggregates.
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.
Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University, Yokohama, Kanagawa 223-8522, Japan.
Yasushi
Y
Mitomi
Takao
T
Nomura
Masaru
M
Kurosawa
Nobuyuki
N
Nukina
Yoshiaki
Y
Furukawa
D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000737:chemistry* / Q000494:pharmacology; D008715:Methionine / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics; D016877:Oxidants / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D011499:Protein Processing, Post-Translational
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D016877:Oxidants; D003300:Copper; D008715:Methionine; D006861:Hydrogen Peroxide