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J Phys Chem Lett. 2015 Jul 2;6(13):2608-15. doi: 10.1021/acs.jpclett.5b00918. Epub 2015 Jun 22.

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

Author information

1
†Instituto de Química Física Rocasolano, CSIC Serrano 119, 28006 Madrid, Spain.
2
‡Instituto Cajal, CSIC Avda, Doctor Arce 37, E-28002 Madrid, Spain.
3
§Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA-Nanociencia), Crta. de Cantoblanco no. 8, E-28049 Cantoblanco, Madrid, Spain.
4
∥Department of Chemistry, Columbia University, 344 Havemeyer Hall, New York, New York 10027, United States.
5
⊥Department of Biological Sciences, Columbia University, New York, New York 10027, United States.
6
#International Centre for Genetic Engineering and Biotechnology, Padriciano 99, I-34149 Trieste, Italy.

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 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.

KEYWORDS:

X-ray diffraction; amyloid; amyotrophic lateral schlerosis; cross-beta spine; molecular dynamics

PMID:
26266742
PMCID:
PMC5568655
DOI:
10.1021/acs.jpclett.5b00918
[Indexed for MEDLINE]
Free PMC Article

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