"A Novel Structure of a Cross-Beta Spine Implicated in Amyotrophic Lateral Sclerosis"
Miguel Mompeán
Miércoles 11 de febrero
Salón de actos, 12:00
"A Novel Structure of a Cross-Beta Spine Implicated in Amyotrophic Lateral Sclerosis"
Miguel Mompeán
Miércoles 11 de febrero
Salón de actos, 12:00
TDP-43 is a large protein that can form pathological aggregates, linked to several neurodegenerative diseases such as ALS and FTLD. Regarding this issue, it has been reported that repeats of the 341-366 segment can recruit endogenous TDP-43 into aggregates inside cells and induce strong loss-of-function effects at the level of RNA metabolism. Recently, we have shown that structural transformation of the short peptide corresponding to TDP-43 residues 341-357 from random coil to beta-hairpin enables oligomerization and is linked to pathology. However, the structure(s) of the aggregate(s) that are formed and their formation dynamics are yet unknown. Here, we use several biophysical, biochemical and computational approaches to characterize and assemble plausible structural models of TDP-43(341-357) aggregates. These aggregates were found to have many characteristics of amyloid-like fibrils including ssNMR signals indicative of beta-structure and X-ray diffraction peaks at 4.6 and 8.6 Å. Based on these experimental findings, structural models for TDP-43(341-357) oligomers were constructed, refined and verified, and analyzed using docking, Molecular Dynamics and Quantum Mechanics computational methods. Interestingly, TDP-43(341-357) adopts a cross-beta spine structure, with cooperative H-bonding and precise side chain intermeshing, built up by a novel mode of lateral association of beta-hairpins, which shares some features of the very recently proposed "beta-turn” model for polyQ fibrils and is quite distinct from the "beta-arc” configuration of beta-hairpins in Abeta1-40, IAPP and a previous model for polyQs. The results of this study will be useful to search for specific strategies to slow down or inhibit TDP-43 aggregation in a pathological setting.