DnaJB1 chaperone inhibits tau aggregation by recognizing its N-terminus

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Protein homeostasis is vital, maintained by folding and degradation systems.
• Misfolded proteins aggregate into amyloid fibrils, implicated in neurodegenerative diseases.
• Selective recognition of pathological aggregates by chaperones remains poorly understood.

Purpose of the Study:

• To elucidate the molecular mechanism of DnaJB1 binding to pathological tau aggregates.
• To investigate how this interaction influences tau assembly and aggregation.
• To identify potential binding sites on DnaJB1 for tau.

Main Methods:

• In vitro biochemical assays to study DnaJB1-tau interactions.
• Cellular models of tau aggregation.
• Analysis of binding dependence on charged residues and polyanionic factors.
• Structural insights into chaperone-substrate recognition.

Main Results:

• DnaJB1 selectively binds pathological tau aggregates through the N-terminus of tau.
• This interaction inhibits tau aggregation in cellular models and in vitro.
• Binding is dependent on negatively charged residues and can be enhanced by polyanions like heparin.
• Identified potential binding sites on DnaJB1, including the J-domain and hinge region.

Conclusions:

• DnaJB1 recognizes pathological tau aggregates via a specific interaction with tau's N-terminus.
• This chaperone-mediated recognition plays a role in regulating tau assembly and inhibiting aggregation.
• Findings provide novel insights into chaperone function in proteinopathies and potential therapeutic strategies.