Mechanism underlying liquid-to-solid phase transition in fused in sarcoma liquid droplets

Abstract

The RNA-binding protein fused in sarcoma (FUS) forms ribonucleoprotein granules via liquid-liquid phase separation (LLPS) in the cytoplasm. The phase separation of FUS accelerates aberrant liquid-solid phase separation and leads...

Liquid–liquid phase separation in synaptopathies

“…Increasing evidence shows that many proteins involved in pathological aggregation in neurodegenerative disorders can undergo phase separation, and protein aggregation can be triggered by aberrant phase separation. There is evidence for this with tau in AD, 69,70 α‐synuclein in PD, 71 huntingtin protein in Huntington's disease, 113 and FUS and TDP‐43 in ALS 1,114 . These findings improve our understanding of phase separation and neurodegenerative disorders and provide a new framework for studying the mechanisms of improperly regulated protein aggregates in neurodegenerative disorders.…”

Elucidating the reversible and irreversible self-assembly mechanisms of low-complexity aromatic-rich kinked peptides and steric zipper peptides

“…[26][27][28] On the other hand, LLPS plays a critical role in the formation of toxic aggregates in diseases such as amyotrophic lateral sclerosis (ALS) [29][30][31][32][33] and frontotemporal lobar degeneration (FTLD). [34][35][36][37] Under abnormal conditions, such as mutations or continuous external stimuli, the droplets formed via LLPS can turn into solid fibrillary aggregates, a process which is called liquid-to-solid phase transition (LSPT). 30,37 The amyloid fibrils are a common end-stage product of LSPT.…”

“…[34][35][36][37] Under abnormal conditions, such as mutations or continuous external stimuli, the droplets formed via LLPS can turn into solid fibrillary aggregates, a process which is called liquid-to-solid phase transition (LSPT). 30,37 The amyloid fibrils are a common end-stage product of LSPT. 7 Recently, the structure of the reversible fibril formed by the fibril core of the FUS low complexity (FUS LC) domain has been determined by solid state nuclear magnetic resonance (ssNMR).…”

“…39 Unlike the irreversible fibrils, the structures of reversible fibrils are organized in kinked strands perpendicular to the fibril spine, or extended β-strands with a hydrous sheet interface, or a stacking pattern with Asp residues from individual β-strands aligned along the fibril spine. 7,12,13,16 For example, fibrils of FUS [37][38][39][40][41][42] (PDB ID: 5XSG) comprise kinked strands without extended β sheets (Fig. S1A †), and fibrils of FUS [54][55][56][57][58][59] (PDB ID: 5XRR) consist of pairs of β-sheets with a hydrophilic interface (Fig.…”

Phase separation by biopolymers: Basics and applications

“…The invited speakers at the symposium will be Ryo Kitahara, Akira Nomoto, Shinji Kajimoto, Kiyoto Kamagata, and Tomoshi Kameda. Kitahara et al will introduce a pressure-temperature phase diagram of LLPS for fused in sarcoma (FUS) and the application of a pressure-jump spectroscopic technique to study the formation and vanishing dynamics of FUS-LLPS [ 6 , 7 ]. Nomoto et al will discuss the solubility parameters of amino acids during LLPS and the aggregation of proteins, based on the solubility of aromatic amino acids in a solution containing 20 different amino acids [ 5 ].…”