Structural Insights into the Coaggregation Mechanism of TTR and TDP

Abstract The self-aggregation of TTR and TDP proteins is closely associated with the treatment of TDP-43 proteinopathies. Recent experimental evidence suggests that TTR and TDP-43 can coaggregate in the cytoplasm of Amyotrophic lateral sclerosis (ALS) patients and disease models. However, their coaggregation molecular mechanisms are unknown. Herein, we investigated the conformational ensembles of TTR, TDP, and TTR-TDP systems, respectively, employing all-atom replica exchange molecular dynamics (REMD), molecular dynamics (MD), and coarse grain (CG) MD simulation methods. Analyses reveal that TTR-TDP heterohexamer can assemble into closed/open β-barrel structures, but TTR/TDP homohexamer can form bilayer structures, implying the distinct coaggregation property of the TTR-TDP heterohexamer. Compared to TTR/TDP systems, the TTR-TDP system has a higher β-sheet content, longer β-strands and larger β-sheets, suggesting the stronger coaggregation ability of the TTR-TDP heterohexamer. Further analyses reveal that the hydrophobic interactions play the pivotal role in driving the coaggregation of TTR and TDP. These findings may provide a deeper understanding of the pathogenesis of related amyloid diseases and prove the development of novel therapeutic strategies.