Molecular Interactions between Tau Protein and TIA1: Distinguishing Physiological Condensates from Pathological...

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• The interaction between tau protein and stress granule proteins is crucial for cellular function and disease.
• Alzheimer's disease is linked to tau pathology and stress granule dysregulation.
• The precise molecular mechanisms governing tau's interaction with TIA1 remain largely unknown.

Purpose of the Study:

• To investigate how the structural state of TIA1 (stress granule condensate vs. fibril) influences its interaction with tau protein.
• To elucidate the molecular details of tau-TIA1 association under different TIA1 structural conformations.

Main Methods:

• Utilized three-repeat constructs of tau (K19) and full-length TIA1 (TIA1-FL) condensates.
• Examined tau aggregation kinetics with TIA1 low-complexity domain (TIA1-LCD) fibrils.
• Employed biophysical techniques, including relaxation-based solution NMR spectroscopy.

Main Results:

• Tau protein (K19) showed reduced dynamics and weak interaction within TIA1-FL condensates.
• Significant interaction was observed between K19 and TIA1-LCD fibrils.
• Specific regions (³²¹KCGS³²⁴ and ³⁰⁶VQIVYKPVDLSKV³¹⁷) mediated the K19-TIA1-LCD fibril interaction.

Conclusions:

• The structural state of TIA1 critically dictates its interaction with tau protein.
• Tau's interaction is distinct in physiological TIA1 condensates versus pathological TIA1 fibrils.
• Understanding these differential interactions is key to comprehending tau's role in neurodegenerative diseases.