TY - JOUR T1 - RNA Stores Tau Reversibly in Complex Coacervates JF - bioRxiv DO - 10.1101/111245 SP - 111245 AU - Xuemei Zhang AU - Neil A. Eschmann AU - Yanxian Lin AU - Hongjun Zhou AU - Jennifer Rauch AU - Israel Hernandez AU - Elmer Guzman AU - Kenneth S. Kosik AU - Songi Han Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/02/24/111245.abstract N2 - 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. ER -