期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-28797-5
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资金
- IISER Mohali, Department of Science and Technology [SR/NM/NS-1475/2014, SR/FST/LS-II/2017/97]
- Science and Engineering Research Board (SUPRA) [SPR/2020/000333]
- Department of Biotechnology
- Council of Scientific and Industrial Research
- Ministry of Education, Govt. of India (Centre of Excellence grant) [MHRD-14-0064]
The phase separation of prion protein and alpha-synuclein through domain-specific electrostatic interactions results in the formation of complex coacervates. These coacervates display electrostatic nanoclusters and can convert into multiphasic condensates and amyloids.
Biomolecular condensation via liquid-liquid phase separation of proteins and nucleic acids is associated with a range of critical cellular functions and neurodegenerative diseases. Here, we demonstrate that complex coacervation of the prion protein and alpha-synuclein within narrow stoichiometry results in the formation of highly dynamic, reversible, thermo-responsive liquid droplets via domain-specific electrostatic interactions between the positively-charged intrinsically disordered N-terminal segment of prion and the acidic C-terminal tail of alpha-synuclein. The addition of RNA to these coacervates yields multiphasic, vesicle-like, hollow condensates. Picosecond time-resolved measurements revealed the presence of transient electrostatic nanoclusters that are stable on the nanosecond timescale and can undergo breaking-and-making of interactions on slower timescales giving rise to a liquid-like behavior in the mesoscopic regime. The liquid-to-solid transition drives a rapid conversion of complex coacervates into heterotypic amyloids. Our results suggest that synergistic prion-alpha-synuclein interactions within condensates provide mechanistic underpinnings of their physiological role and overlapping neuropathological features. The authors show that prion protein and alpha-synuclein undergo phase separation through domain-specific electrostatic interactions. These complex coacervates possess electrostatic nanoclusters and can convert into multiphasic condensates and amyloids.
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