Mechanism of amyloid disassembly by the human Hsp70 chaperone network
Pr Bernd BUKAU
Zentrum für Molekulare Biologie der Universität Heidelberg, Germany
Tuesday, September 24th 2019 - 11 a.m.
- Auditorium, IGBMC
Hosted by Integrated structural Biology, Helgo SCHMIDT
Parkinson’s disease (PD) is a debilitating neurodegenerative condition linked to the gradual accumulation of α-synuclein amyloid inclusions in the brain. The progressive conversion of monomeric soluble α-synuclein into toxic oligomeric and fibrillar species results in the formation of highly stable, ordered aggregates that constitute atypical substrates for the cellular protein quality control machinery. The constitutive human Hsp70 chaperone (Hsc70), assisted by co-chaperones DNAJB1 and Apg2, generates a powerful ATP-dependent disaggregation activity that efficiently resolubilizes α-synuclein amyloid fibrils in vitro. Combining NMR spectroscopy, equilibrium and kinetic binding experiments and disaggregation activity assays, we dissect the functional cycle of Hsc70 to build a detailed picture of chaperone action on an amyloid substrate. Our data provide crucial new insights into the mode of action of Hsc70 on amyloid fibrils and highlights the essential role of co-chaperones in the activity of Hsc70.