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Structure. 2017 Jun 6;25(6):846-857.e4. doi: 10.1016/j.str.2017.04.001. Epub 2017 May 4.

The Highly Dynamic Nature of ERdj5 Is Key to Efficient Elimination of Aberrant Protein Oligomers through ER-Associated Degradation.

Author information

1
Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Katahira 2-1-1, Aoba-ku, Sendai 980-8577, Japan; CREST, JST, Japan.
2
Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan; CREST, JST, Japan.
3
Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Katahira 2-1-1, Aoba-ku, Sendai 980-8577, Japan.
4
Department of Molecular Biosciences, Kyoto Sangyo University, Kyoto 603-8455, Japan; CREST, JST, Japan.
5
Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Katahira 2-1-1, Aoba-ku, Sendai 980-8577, Japan; CREST, JST, Japan. Electronic address: kinaba@tagen.tohoku.ac.jp.

Abstract

ERdj5, composed of an N-terminal J domain followed by six thioredoxin-like domains, is the largest protein disulfide isomerase family member and functions as an ER-localized disulfide reductase that enhances ER-associated degradation (ERAD). Our previous studies indicated that ERdj5 comprises two regions, the N- and C-terminal clusters, separated by a linker loop and with distinct functional roles in ERAD. We here present a new crystal structure of ERdj5 with a largely different cluster arrangement relative to that in the original crystal structure. Single-molecule observation by high-speed atomic force microscopy visualized rapid cluster movement around the flexible linker loop, indicating the highly dynamic nature of ERdj5 in solution. ERdj5 mutants with a fixed-cluster orientation compromised the ERAD enhancement activity, likely because of less-efficient reduction of aberrantly formed disulfide bonds and prevented substrate transfer in the ERdj5-mediated ERAD pathway. We propose a significant role of ERdj5 conformational dynamics in ERAD of disulfide-linked oligomers.

KEYWORDS:

ERAD; ERdj5; X-ray crystal structure analysis; high-speed AFM; single-molecule analysis

PMID:
28479060
DOI:
10.1016/j.str.2017.04.001
[Indexed for MEDLINE]
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