Hernández-Vega A, Braun M, Scharrel L, Jahnel M, Wegmann S, Hyman BT, Alberti S, Diez S, Hyman AA. Local Nucleation of Microtubule Bundles through Tubulin Concentration into a Condensed Tau Phase. Cell Rep. 2017 Sep 5;20(10):2304-2312. PubMed.
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University of California, Santa Barbara
Liquid-liquid phase separation (LLPS) of intrinsically disordered, low-complexity proteins is a widespread biophysical phenomenon, and recently has been extended to include the microtubule binding protein tau. The most pressing and unresolved questions facing the studies of LLPS is its physiological role in vivo. The study by Hernandez-Vega et al. shows that tau from insect cells, which is highly phosphorylated, is capable of self-coacervating under conditions of molecular crowding. LLPS was enhanced in the presence of tubulin, as well as RNA, both of which are polyanions. Most strikingly, tubulin favorably partitioned into the droplet phase of tau, and microtubule polymerization was promoted within this phase containing high local concentrations of tubulin and tau. Polymerization occurred even when tubulin was added under droplet-forming conditions at a concentration an order of magnitude lower than typically critical for polymerization. Moreover, Hernandez-Vega et al. convincingly demonstrate that the role of tau droplets is not just that of a protein concentrator, but that of actively promoting elongation and growth of tubulin polymerization. The mechanism of the latter remains to be understood, but is generally assumed to be due to the effects of confinement and diffusion-limited reaction processes. The mechanics of such reactions have been modeled by the reaction-diffusion master equation used to study biochemical reactions in living cells (Hellander and Petzold, 2017).
The presence of heparin deactivated tubulin polymerization. We believe this was due to competitive binding of the polyanion, heparin, which more favorably binds to tau than does tubulin or RNA.
The question of the physiological role of tau droplets, and for that matter all LLPS processes, is still an open one. However, this study opens up another possibility, namely that of regulating non-centrosomal cytoskeleton polymerization and microtubule bundling. This is a complementary thesis to that of Ambadipudi et al., who proposed that tau droplet formation is a precursor and intermediate phase toward pathological tau aggregation, and that by Zhang et al., that makes similar observations as in Ambadipudi et al. to propose that tau droplet formation is initially protecting and sequestering tau from aggregation (Ambadipudi et al. 2017; Zhang et al., 2017).
Songi Han of the University of California Santa Barbara is the co-author of this comment.
References:
Hellander S, Petzold L. Reaction rates for reaction-diffusion kinetics on unstructured meshes. J Chem Phys. 2017 Feb 14;146(6):064101. PubMed.
Ambadipudi S, Biernat J, Riedel D, Mandelkow E, Zweckstetter M. Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau. Nat Commun. 2017 Aug 17;8(1):275. PubMed.
Zhang X, Lin Y, Eschmann NA, Zhou H, Rauch JN, Hernandez I, Guzman E, Kosik KS, Han S. RNA stores tau reversibly in complex coacervates. PLoS Biol. 2017 Jul;15(7):e2002183. Epub 2017 Jul 6 PubMed.
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