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Conformational changes specific for pseudophosphorylation at serine 262 selectively impair binding of tau to

Daniela Fischer1, Marco D Mukrasch, Jacek Biernat

  • 1Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany.

Biochemistry
|September 23, 2009
PubMed

Insights

Phosphorylation of tau protein alters its structure, impacting its function in the brain. This study mimicked tau phosphorylation to understand its role in neurodegenerative diseases like Alzheimer's.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Neurofibrillary tangles, formed by tau protein aggregation, are key indicators of dementia.
  • In Alzheimer's disease, tau protein becomes hyperphosphorylated, disrupting its microtubule binding.
  • The repeat region of tau (K18) is crucial for microtubule assembly and forms the core of pathological filaments.

Purpose of the Study:

  • To investigate how phosphorylation affects the conformational and binding properties of the tau K18 repeat region.
  • To understand the structural basis of tau's altered function in neurodegenerative diseases.

Main Methods:

  • Mimicking tau phosphorylation by introducing serine to glutamate mutations at key sites (262, 293, 324, 356).
  • Utilizing Nuclear Magnetic Resonance (NMR) spectroscopy to analyze structural changes in the modified tau repeat region.

Main Results:

  • Pseudophosphorylation induced significant structural modifications in tau repeats 1 and 2, particularly the Gln265-Lys267 region.
  • These changes occurred near Ser262, a site critical for attenuating microtubule binding.
  • The pseudophosphorylated tau mimic showed enhanced interaction with heparin, a polyanion.

Conclusions:

  • Phosphorylation of the tau repeat region induces specific conformational changes in the natively unfolded protein.
  • These alterations significantly impact tau's biological function and its role in the pathogenesis of dementia.
  • Understanding these phosphorylation-induced changes is vital for developing therapeutic strategies for tauopathies.

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