Structure challenges in the multivalency of Tau-microtubule interactions

Area of Science:

• Neuroscience
• Structural Biology
• Biochemistry

Background:

• Tau protein interactions with microtubules (MTs) are crucial for neuronal function.
• Tau has multiple MT-binding regions (repeats) that interact with MT lattice elements.
• The non-identical nature of Tau repeats and their binding to MTs complicates structural analysis.

Purpose of the Study:

• To address the challenges in visualizing Tau-microtubule interactions using cryo-electron microscopy (cryo-EM).
• To discuss methods for overcoming these challenges to achieve an atomic-level understanding of Tau-tubulin binding.

Main Methods:

• Cryo-electron microscopy (cryo-EM) for structural visualization.
• Analysis of image data considering the complexities of Tau repeat binding.
• Commentary on existing and potential methodologies.

Main Results:

• Identified significant challenges in cryo-EM image analysis due to Tau's multiple, non-registering MT-binding repeats.
• Highlighted the variability in Tau molecule engagement with MTs (using single or multiple repeats).

Conclusions:

• Conventional image analysis methods are insufficient for atomic-level visualization of Tau-MT interactions.
• Novel approaches are needed to accurately describe the structural basis of Tau binding to microtubules.