Cross-seeding and conformational selection between three- and four-repeat human Tau proteins.

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Paired helical filaments of microtubule-associated protein Tau are implicated in Alzheimer's disease and frontotemporal dementias.
• Both full-length Tau and its segments, such as K18 (four repeats) and K19 (three repeats), can form these filaments.
• Experimental evidence shows K19 can seed K18 aggregation, but not vice versa, indicating an asymmetric cross-seeding process.

Purpose of the Study:

• To investigate the structural basis of cross-seeding between K18 and K19 Tau segments.
• To understand how different conformations and repeat structures influence the co-assembly of heterogeneous Tau filaments.

Main Methods:

• Computational assembly of K18 and K19 octamers with repeat 3 (R3) in various conformations (U-shaped, L-shaped, SL-shaped).
• Analysis of populated structures and their similarity to understand potential co-assembly cores.
• Identification of critical structural features for K18 and K19 aggregation and fibrillization.

Main Results:

• Highly populated K18 and K19 octamers with R3 in L-shaped and SL-shaped conformations exhibited significant structural similarity.
• This structural similarity suggests a potential common core for K18-K19 co-assembled filaments.
• Stable R2 and R3 conformations are crucial for K18 aggregation, while R3 is critical for K19 fibrillization, highlighting differing structural requirements.
• The absence of R2 in K19 may create a cross-seeding barrier, explaining the asymmetry observed experimentally.

Conclusions:

• Similar folding patterns in K18/K19 segments can facilitate the formation of heterogeneous Tau filaments.
• Differences in critical structural units (R2 and R3 availability) between K18 and K19 lead to an asymmetric cross-seeding barrier.
• The polymorphic nature of protein aggregation is amplified in cross-seeding, and significant divergence in seeding conformations can impede fibril formation.