RT Journal Article
SR Electronic
T1 RNA Stores Tau Reversibly in Complex Coacervates
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 111245
DO 10.1101/111245
A1 Xuemei Zhang
A1 Neil A. Eschmann
A1 Yanxian Lin
A1 Hongjun Zhou
A1 Jennifer Rauch
A1 Israel Hernandez
A1 Elmer Guzman
A1 Kenneth S. Kosik
A1 Songi Han
YR 2017
UL http://biorxiv.org/content/early/2017/02/24/111245.abstract
AB Non-membrane bound organelles that behave like liquid droplets are widespread among eukaryotic cells. Their dysregulation appears to be a critical step in several neurodegenerative conditions. Here we report that Tau protein, the primary constituent of Alzheimer neurofibrillary tangles, can form liquid droplets and therefore has the necessary biophysical properties to undergo a liquid-liquid phase separation (LLPS) in cells. Consonant with the factors that induce LLPS, Tau is an intrinsically disordered protein that electrostatically complexes with RNA to form droplets that can be tuned by salt concentration and temperature and exhibit low interfacial tension. Uniquely, the pool of RNAs to which Tau binds in living cells are tRNAs. This phase state of Tau is held in 1:1 charge balance across large blocks of the protein and the nucleic acid and forms optimal complexes at multiple RNA:Tau mass ratios. These features define a complex co-acervate in which undergo free diffusion in their interior, despite the high concentration of protein, and rapid exchange with their exterior environment. Counter to most closely packed protein assemblies, the condensed phase state of Tau is not associated with changes in local Tau conformations as verified by distance measurements across a pair of spin labels by pulsed dipolar spectroscopy. In contrast, fibrillar states of Tau are accompanied by large changes in local Tau conformations. Importantly, prolonged residency within a droplet results in the emergence of detectable beta-structure by thioflavin labeling, suggesting that the droplet state can incubate Tau and pre-dispose it toward beta sheet structures typical of insoluble Tau fibrils.