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

ABSTRACT: TDP-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 ?-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) ?-hairpins assemble into a novel parallel ?-turn configuration showing cross-? 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.

SUBMITTER: Mompean M 

PROVIDER: S-EPMC5568655 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Mompeán Miguel M   Hervás Rubén R   Xu Yunyao Y   Tran Timothy H TH   Guarnaccia Corrado C   Buratti Emanuele E   Baralle Francisco F   Tong Liang L   Carrión-Vázquez Mariano M   McDermott Ann E AE   Laurents Douglas V DV  

The journal of physical chemistry letters 20150622 13

TDP-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 extens  ...[more]

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