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Structural Evidence of Amyloid Fibril Formation in the Putative Aggregation Domain of TDP-43

AutorMompeán, M.; Hervás, Rubén ; Xu, Y.; Tran, T.H.; Guarnaccia, C.; Buratti, E.; Baralle, F.; Tong, L.; Carrión-Vázquez, Mariano Sixto ; McDermott, A.E.; Laurents, D.V.
Fecha de publicación2015
CitaciónJournal of Physical Chemistry Letters 6: 2608- 2615 (2015)
ResumenTDP-43 can form pathological proteinaceous aggregates linked to ALS and FTLD. Within the putative aggregation domain, engineered repeats of residues 341-366 can recruit endogenous TDP-43 into aggregates inside cells; however, the nature of these aggregates is a debatable issue. Recently, we showed that a coil to β-hairpin transition in a short peptide corresponding to TDP-43 residues 341-357 enables oligomerization. Here we provide definitive structural evidence for amyloid formation upon extensive characterization of TDP-43(341-357) via chromophore and antibody binding, electron microscopy (EM), solid-state NMR, and X-ray diffraction. On the basis of these findings, structural models for TDP-43(341-357) oligomers were constructed, refined, verified, and analyzed using docking, molecular dynamics, and semiempirical quantum mechanics methods. Interestingly, TDP-43(341-357) β-hairpins assemble into a novel parallel β-turn configuration showing cross-β spine, cooperative H-bonding, and tight side-chain packing. These results expand the amyloid foldome and could guide the development of future therapeutics to prevent this structural conversion.
Identificadoresdoi: 10.1021/acs.jpclett.5b00918
issn: 1948-7185
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