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Nat Commun. 2015 Jan 20;6:6116. doi: 10.1038/ncomms7116.

The unexpected role of polyubiquitin chains in the formation of fibrillar aggregates.

Author information

1
Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto-Daigaku Katsura, Nishikyo-Ku, Kyoto 615-8510, Japan.
2
Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Naka-ku, Sakai, Osaka 599-8531, Japan.
3
Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
4
1] Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Department of Biochemistry, School of Medicine, Niigata University, Chuo-ku, Niigata 951-8510, Japan.
5
Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi, Sakyo-ku, Kyoto 606-8501, Japan.
6
Quantitative Biology Center, RIKEN, 1-3 OLABB, Osaka University 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan.
7
Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
8
Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
9
Department of Biophysics, Graduate School of Science, Kyoto University, Oiwake-cho, Kitashirakawa, Sakyo-Ku, Kyoto 606-8502, Japan.
10
Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
11
1] Quantitative Biology Center, RIKEN, 1-3 OLABB, Osaka University 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan [2] Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.

Abstract

Ubiquitin is known to be one of the most soluble and stably folded intracellular proteins, but it is often found in inclusion bodies associated with various diseases including neurodegenerative disorders and cancer. To gain insight into this contradictory behaviour, we have examined the physicochemical properties of ubiquitin and its polymeric chains that lead to aggregate formation. We find that the folding stability of ubiquitin chains unexpectedly decreases with increasing chain length, resulting in the formation of amyloid-like fibrils. Furthermore, when expressed in cells, polyubiquitin chains covalently linked to EGFP also form aggregates depending on chain length. Notably, these aggregates are selectively degraded by autophagy. We propose a novel model in which the physical and chemical instability of polyubiquitin chains drives the formation of fibrils, which then serve as an initiation signal for autophagy.

PMID:
25600778
PMCID:
PMC4309437
DOI:
10.1038/ncomms7116
[Indexed for MEDLINE]
Free PMC Article

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