Exploring the Aggregation-prone regions from structural domains of. Human TDP-43

In this study, we attempted to delineate the aggregation-prone sequences of the structural domain of TDP-43. Here, we investigated the self-assembly of peptides of TDP-43 using aggregation prediction algorithms, Zipper DB and AMYLPRED2. The three aggregation-prone peptides identified were from N-terminal domain (24GTVLLSTV31), and RNA recognition motifs, RRM1 (128GEVLMVQV135) and RRM2 (247DLIIKGIS254). Furthermore, the amyloid fibril forming propensities of these peptides were analyzed through different biophysical techniques and molecular dynamics simulation. Our study shows the different aggregation ability of conserved stretches in structural domain of TDP-43 that will possibly induce full-length aggregation of TDP-43 in vivo. The peptide form RRM2 demonstrates the higher intrinsic amyloid forming propensity and suggests that RRM2 might form the structural core of TDP-43 aggregation seen in vivo. The results of this study would help in designing peptide based inhibitors of TDP-43 aggregation.Graphical abstract

Source: Biochimica et Biophysica Acta (BBA) Proteins and Proteomics - October 12, 2018 Category: Biochemistry Source Type: research