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Human Hsp70 Disaggregase Reverses Parkinson’s-Linked α-Synuclein Amyloid Fibrils
- Source :
- Molecular Cell. 59:781-793
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- Intracellular amyloid fibrils linked to neurodegenerative disease typically accumulate in an age-related manner, suggesting inherent cellular capacity for counteracting amyloid formation in early life. Metazoan molecular chaperones assist native folding and block polymerization of amyloidogenic proteins, preempting amyloid fibril formation. Chaperone capacity for amyloid disassembly, however, is unclear. Here, we show that a specific combination of human Hsp70 disaggregase-associated chaperone components efficiently disassembles α-synuclein amyloid fibrils characteristic of Parkinson’s disease in vitro. Specifically, the Hsc70 chaperone, the class B J-protein DNAJB1, and an Hsp110 family nucleotide exchange factor (NEF) provide ATP-dependent activity that disassembles amyloids within minutes via combined fibril fragmentation and depolymerization. This ultimately generates non-toxic α-synuclein monomers. Concerted, rapid interaction cycles of all three chaperone components with fibrils generate the power stroke required for disassembly. This identifies a powerful human Hsp70 disaggregase activity that efficiently disassembles amyloid fibrils and points to crucial yet undefined biology underlying amyloid-based diseases.
- Subjects :
- Amyloid
Electron Microscope Tomography
macromolecular substances
In Vitro Techniques
Protein aggregation
bcs
Fibril
Protein Aggregation, Pathological
Article
Nucleotide exchange factor
Protein Aggregates
chemistry.chemical_compound
mental disorders
Humans
HSP70 Heat-Shock Proteins
HSP110 Heat-Shock Proteins
Molecular Biology
Alpha-synuclein
biology
HSC70 Heat-Shock Proteins
P3 peptide
Parkinson Disease
Cell Biology
HSP40 Heat-Shock Proteins
Cell biology
Kinetics
Solubility
chemistry
Biochemistry
Chaperone (protein)
alpha-Synuclein
biology.protein
Protein Multimerization
Intracellular
Molecular Chaperones
Subjects
Details
- ISSN :
- 10972765
- Volume :
- 59
- Database :
- OpenAIRE
- Journal :
- Molecular Cell
- Accession number :
- edsair.doi.dedup.....b18b791d24e37aad21186a6dcc3fb017