Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic Inclusion

Jiang, Lei; Xia, Mei; Zhao, Jian; Zhou, Chen; Xie, Mu Yun; Li, Hai Yin; He, Jian; Hu, Hong Yu

doi:10.1074/jbc.m113.463828

Cited by 129 publications

(194 citation statements)

References 47 publications

(49 reference statements)

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“…Specifically, segment 286–331 has been shown to form amyloid fibrils and confer neurotoxicity on primary cortical neurons 41 . Residues 311–360 have been proposed to be the amyloid core through NMR and CD studies 42,43 . Finally, it has been shown that residues 341–367 can drive pathological aggregation of TDP-43 in neuronal cell lines 44 , residues 342–366 transition from a random coil to a β-sheet 45 , and that deletion of residues 318–343 delays aggregation of full-length TDP-43 (ref.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, it has been shown that residues 341–367 can drive pathological aggregation of TDP-43 in neuronal cell lines 44 , residues 342–366 transition from a random coil to a β-sheet 45 , and that deletion of residues 318–343 delays aggregation of full-length TDP-43 (ref. 42 ). These findings offer strong support for the role of the C terminus in TDP-43 aggregation.…”

Section: Resultsmentioning

confidence: 99%

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Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2

Guenther

Trinh

et al. 2018

Nat Struct Mol Biol

107

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Proteins in the fibrous amyloid state are a major hallmark of neurodegenerative disease. Understanding the multiple conformations, or polymorphs, of amyloid proteins at the molecular level is a challenge of amyloid research. Here, we detail the wide range of polymorphs formed by a segment of human TAR DNA-binding protein 43 (TDP-43) as a model for the polymorphic capabilities of pathological amyloid aggregation. Using X-ray diffraction, microelectron diffraction (MicroED) and single-particle cryo-EM, we show that the 247DLIIKGISVHI257 segment from the second RNA-recognition motif (RRM2) forms an array of amyloid polymorphs. These associations include seven distinct interfaces displaying five different symmetry classes of steric zippers. Additionally, we find that this segment can adopt three different backbone conformations that contribute to its polymorphic capabilities. The polymorphic nature of this segment illustrates at the molecular level how amyloid proteins can form diverse fibril structures.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2

Guenther

Trinh

et al. 2018

Nat Struct Mol Biol

107

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“…6–8 Despite the dominant role of the cross-β-sheet in mature fibrils, 9–11 compelling evidence points to an intermediate role for the α-helix in the cascade. 12–15 Many aggregating proteins exhibit α-helical character when associated with membrane. 15–17 However, the crowded environment in cells makes the study of in vivo aggregation challenging.…”

Section: Introductionmentioning

confidence: 99%

Elucidation of the Aggregation Pathways of Helix–Turn–Helix Peptides: Stabilization at the Turn Region Is Critical for Fibril Formation

Thanh¹,

Chamas²,

Zheng³

et al. 2015

Biochemistry

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Aggregation of proteins to fiber-like aggregates often involves a transformation of native monomers to β-sheet-rich oligomers. This general observation underestimates the importance of α-helical segments in the aggregation cascade. Here, using a combination of experimental techniques and accelerated molecular dynamics simulations, we investigate the aggregation of a 43-residue, apolipoprotein A-I mimetic peptide and its E21Q and D26N mutants. Our study indicates a strong propensity of helical segments not to adopt cross-β fibrils. The helix-turn-helix monomeric conformation of the peptides is preserved in the mature fibrils. Furthermore, we reveal opposite effects of mutations on and near the turn region in the self-assembly of these peptides. We show that the E21-R24 salt bridge is a major contributor to helix-turn-helix folding, subsequently leading to abundant fibril formation. On the other hand, the K19-D26 interaction is not required to fold the native helix-turn-helix. However, removal of the charged D26 residue decreases the stability of helix-turn-helix monomer, and consequently reduces aggregation. Finally, we provide a more refined assembly model for the helix-turn-helix peptides from apolipoprotein A-I based on the parallel stacking of helix-turn-helix dimers.

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“…There is an open debate and contrasting results regarding whether the toxic aggregate is amorphous [4] or amyloid-like [9,10] and which segment is key for its formation [11][12][13][14]. We have recently shown that tandem repeats of the C-terminal segment enriched with Asn and Gln residues can reproduce almost all the disease hallmarks of the full-length protein in cells [15].…”

mentioning

confidence: 99%

The TDP‐43 N‐terminal domain structure at high resolution

et al. 2016

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Transactive response DNA-binding protein 43 kDa (TDP-43) is an RNA transporting and processing protein whose aberrant aggregates are implicated in neurodegenerative diseases. The C-terminal domain of this protein plays a key role in mediating this process. However, the N-terminal domain (residues 1-77) is needed to effectively recruit TDP-43 monomers into this aggregate. In the present study, we report, for the first time, the essentially complete 1 H, 15N and 13C NMR assignments and the structure of the N-terminal domain determined on the basis of 26 hydrogen-bond, 60 torsion angle and 1058 unambiguous NOE structural restraints. The structure consists of an a-helix and six b-strands. Two b-strands form a b-hairpin not seen in the ubiquitin fold. All Pro residues are in the trans conformer and the two Cys are reduced and distantly separated on the surface of the protein. The domain has a well defined hydrophobic core composed of F35, Y43, W68, Y73 and 17 aliphatic side chains. The fold is topologically similar to the reported structure of axin 1. The protein is stable and no denatured species are observed at pH 4 and 25°C. At 4 kcalÁmol À1 , the conformational stability of the domain, as measured by hydrogen/deuterium exchange, is comparable to ubiquitin (6 kcalÁmol À1 ).The b-strands, a-helix, and three of four turns are generally rigid, although the loop formed by residues 47-53 is mobile, as determined by model-free analysis of the 15 N{ 1 H}NOE, as well as the translational and transversal relaxation rates.

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Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic Inclusion

Cited by 129 publications

References 47 publications

Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2

Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2

Elucidation of the Aggregation Pathways of Helix–Turn–Helix Peptides: Stabilization at the Turn Region Is Critical for Fibril Formation

The TDP‐43 N‐terminal domain structure at high resolution

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