Journal
STRUCTURE
Volume 25, Issue 6, Pages 846-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2017.04.001
Keywords
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Funding
- CREST, JST [JPMJCR13M6, JPMJCR13M1]
- MEXT [15H04335, 26116005, 15H01626, 15641922]
- Takeda Science Foundation
- Japan Agency for Medical Research and Development (AMED)
- program of the Joint Usage/Research Center for Developmental Medicine
- Institute of Molecular Embryology and Genetics, Kumamoto University
- [13J04030]
- Grants-in-Aid for Scientific Research [17H05675, 15H01626, 26116005, 15H04335] Funding Source: KAKEN
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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.
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