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J Biol Chem. 2019 Mar 29;294(13):4956-4965. doi: 10.1074/jbc.RA118.005980. Epub 2019 Feb 4.

Heat shock protein 104 (HSP104) chaperones soluble Tau via a mechanism distinct from its disaggregase activity.

Author information

1
From the Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
2
the University of the Chinese Academy of Sciences, Shijingshan District, Beijing 100049, China.
3
the Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
4
the Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200030, China, and.
5
the Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China, lixueming@tsinghua.edu.cn.
6
From the Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China, liulab@sioc.ac.cn.

Abstract

Heat shock protein 104 (HSP104) is a conserved AAA+ protein disaggregase, can disassemble the toxic aggregates formed by different amyloid proteins, and is protective in various animal models associated with amyloid-related diseases. Extensive studies have attempted to elucidate how HSP104 disassembles the aggregated form of clients. Here, we found that HSP104 exhibits a potent holdase activity that does not require energy, prevents the soluble form of amyloid clients from aggregating, and differs from HSP104's disaggregase activity. Using cryo-EM, NMR, and additional biophysical approaches, we found that HSP104 utilizes its small subdomain of nucleotide-binding domain 2 (ssNBD2) to capture the soluble amyloid client (K19 of Tau) independent of its ATP hydrolysis activity. Our results indicate that HSP104 utilizes two fundamental distinct mechanisms to chaperone different forms of amyloid client and highlight the important yet previously unappreciated function of ssNBD2 in chaperoning amyloid client and thereby preventing pathological aggregation.

KEYWORDS:

HSP104; Tau protein (Tau); amyloid; chaperone; heat shock protein (HSP); holdase; protein aggregation; protein fibrils

PMID:
30718279
PMCID:
PMC6442063
[Available on 2020-03-29]
DOI:
10.1074/jbc.RA118.005980
[Indexed for MEDLINE]

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