Tau repeat regions contain conserved histidine residues that modulate microtubule-binding in response to changes in pH

Rabab A. Charafeddine, Wilian A. Cortopassi, Parnian Lak, Ruensern Tan, Richard Mckenney, Matthew P. Jacobson, Diane L. Barber, Torsten Wittmann

Research output: Contribution to journalArticle

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Abstract

Tau, a member of the MAP2/tau family of microtubule-associated proteins, stabilizes and organizes axonal microtubules in healthy neurons. In neurodegenerative tauopathies, tau dissociates from microtubules and forms neurotoxic extracellular aggregates. MAP2/tau family proteins are characterized by three to five conserved, intrinsically disordered repeat regions that mediate electrostatic interactions with the microtubule surface. Here, we used molecular dynamics, microtubule-binding experiments, and live-cell microscopy, revealing that highly-conserved histidine residues near the C terminus of each microtubule-binding repeat are pH sensors that can modulate tau–microtubule interaction strength within the physiological intracellular pH range. We observed that at low pH (<7.5), these histidines are positively charged and interact with phenylalanine residues in a hydrophobic cleft between adjacent tubulin dimers. At higher pH (>7.5), tau deprotonation decreased binding to microtubules both in vitro and in cells. Electrostatic and hydrophobic characteristics of histidine were both required for tau–microtubule binding, as substitutions with constitutively and positively charged nonaromatic lysine or uncharged alanine greatly reduced or abolished tau–microtubule binding. Consistent with these findings, tau–microtubule binding was reduced in a cancer cell model with increased intracellular pH but was rapidly restored by decreasing the pH to normal levels. These results add detailed insights into the intracellular regulation of tau activity that may be relevant in both normal and pathological conditions.

Original languageEnglish (US)
Pages (from-to)8779-8790
Number of pages12
JournalJournal of Biological Chemistry
Volume294
Issue number22
DOIs
StatePublished - Jan 1 2019

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Histidine
Microtubules
pH sensors
Deprotonation
Microtubule-Associated Proteins
Coulomb interactions
Alanine
Lysine
Neurons
Molecular dynamics
Electrostatics
Microscopic examination
Substitution reactions
Cells
Static Electricity
Tauopathies
tau Proteins
Proteins
Experiments
Molecular Dynamics Simulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Tau repeat regions contain conserved histidine residues that modulate microtubule-binding in response to changes in pH. / Charafeddine, Rabab A.; Cortopassi, Wilian A.; Lak, Parnian; Tan, Ruensern; Mckenney, Richard; Jacobson, Matthew P.; Barber, Diane L.; Wittmann, Torsten.

In: Journal of Biological Chemistry, Vol. 294, No. 22, 01.01.2019, p. 8779-8790.

Research output: Contribution to journalArticle

Charafeddine, Rabab A. ; Cortopassi, Wilian A. ; Lak, Parnian ; Tan, Ruensern ; Mckenney, Richard ; Jacobson, Matthew P. ; Barber, Diane L. ; Wittmann, Torsten. / Tau repeat regions contain conserved histidine residues that modulate microtubule-binding in response to changes in pH. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 22. pp. 8779-8790.
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