The proline-rich domain promotes Tau liquid-liquid phase separation in cells

Tau protein in vitro can undergo liquid-liquid phase separation (LLPS); however, observations of this phase transition in living cells are limited. To investigate protein state transitions in living cells, we attached Cry2 to Tau and studied the contribution of each domain that drives the Tau cluste...

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Published inThe Journal of cell biology Vol. 219; no. 11; p. 1
Main Authors Zhang, Xuemei, Vigers, Michael, McCarty, James, Rauch, Jennifer N, Fredrickson, Glenn H, Wilson, Maxwell Z, Shea, Joan-Emma, Han, Songi, Kosik, Kenneth S
Format Journal Article
LanguageEnglish
Published United States Rockefeller University Press 02.11.2020
Subjects
Binding
Cell Separation - methods
Cells (biology)
Condensates
Cytoskeleton
Domains
Dynamic stability
Fluorescence
Fluorescence recovery after photobleaching
Humans
Liquid phases
Liquid-Liquid Extraction - methods
Microtubules
Neuroblastoma - metabolism
Neuroblastoma - pathology
Neuroscience
Phase separation
Phase transitions
Phosphorylation
Photobleaching
Proline
Proline - chemistry
Proline - metabolism
Protein Aggregation, Pathological
Protein Binding
Proteins
Tau protein
tau Proteins - chemistry
tau Proteins - metabolism
Tubulin
Tumor Cells, Cultured
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Summary:Tau protein in vitro can undergo liquid-liquid phase separation (LLPS); however, observations of this phase transition in living cells are limited. To investigate protein state transitions in living cells, we attached Cry2 to Tau and studied the contribution of each domain that drives the Tau cluster in living cells. Surprisingly, the proline-rich domain (PRD), not the microtubule binding domain (MTBD), drives LLPS and does so under the control of its phosphorylation state. Readily observable, PRD-derived cytoplasmic condensates underwent fusion and fluorescence recovery after photobleaching consistent with the PRD LLPS in vitro. Simulations demonstrated that the charge properties of the PRD predicted phase separation. Tau PRD formed heterotypic condensates with EB1, a regulator of plus-end microtubule dynamic instability. The specific domain properties of the MTBD and PRD serve distinct but mutually complementary roles that use LLPS in a cellular context to implement emergent functionalities that scale their relationship from binding α-beta tubulin heterodimers to the larger proportions of microtubules.
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J. McCarty’s present address is Department of Chemistry, Western Washington University, Bellingham, WA.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.202006054