Modulating α-Synuclein Liquid–Liquid Phase Separation

化学 生物物理学 内在无序蛋白质 液态液体 动力学 体外 色谱法 生物化学 生物 物理 量子力学
作者
Ajay Singh Sawner,Soumik Ray,Preeti Yadav,Semanti Mukherjee,Rajlaxmi Panigrahi,Manisha Poudyal,Komal Patel,Dhiman Ghosh,Eric Kummerant,Ashutosh Kumar,Roland Riek,Samir K. Maji
出处
期刊:Biochemistry [American Chemical Society]
卷期号:60 (48): 3676-3696 被引量:103
标识
DOI:10.1021/acs.biochem.1c00434
摘要

Liquid-liquid phase separation (LLPS) is a crucial phenomenon for the formation of functional membraneless organelles. However, LLPS is also responsible for protein aggregation in various neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease (PD). Recently, several reports, including ours, have shown that α-synuclein (α-Syn) undergoes LLPS and a subsequent liquid-to-solid phase transition, which leads to amyloid fibril formation. However, how the environmental (and experimental) parameters modulate the α-Syn LLPS remains elusive. Here, we show that in vitro α-Syn LLPS is strongly dependent on the presence of salts, which allows charge neutralization at both terminal segments of protein and therefore promotes hydrophobic interactions supportive for LLPS. Using various purification methods and experimental conditions, we showed, depending upon conditions, α-Syn undergoes either spontaneous (instantaneous) or delayed LLPS. Furthermore, we delineate that the kinetics of liquid droplet formation (i.e., the critical concentration and critical time) is relative and can be modulated by the salt/counterion concentration, pH, presence of surface, PD-associated multivalent cations, and N-terminal acetylation, which are all known to regulate α-Syn aggregation in vitro. Together, our observations suggest that α-Syn LLPS and subsequent liquid-to-solid phase transition could be pathological, which can be triggered only under disease-associated conditions (high critical concentration and/or conditions promoting α-Syn self-assembly). This study will significantly improve our understanding of the molecular mechanisms of α-Syn LLPS and the liquid-to-solid transition.
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