“Structural characterization of the minimal segment of TDP-43 competent for aggregation”

Mompeán, Miguel; Buratti, Emanuele; Guarnaccia, Corrado; Brito, Rui M. M.; Chakrabartty, Avijit; Baralle, Francisco E.; Laurents, Douglas V.

doi:10.1016/j.abb.2014.01.007

Cited by 69 publications

(79 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our own recent results (Budini et al, 2012; Mompeán et al, 2014, 2015) also point to the Q/N-rich segment as being very important for TDP-43 aggregation and amyloid formation. Moreover, the recent mass-spectrometry/proteolysis study of TDP-43 from ex vivo brains of two ALS patients provides insight into the relative importance of the hydrophobic and Q/N rich regions (Kametani et al, 2016).…”

Section: Introductionsupporting

confidence: 54%

See 1 more Smart Citation

An Amyloid-Like Pathological Conformation of TDP-43 Is Stabilized by Hypercooperative Hydrogen Bonds

Mompeán

Baralle

Buratti

et al. 2016

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

TDP-43 is an essential RNA-binding protein forming aggregates in almost all cases of sporadic amyotrophic lateral sclerosis (ALS) and many cases of frontotemporal lobar dementia (FTLD) and other neurodegenerative diseases. TDP-43 consists of a folded N-terminal domain with a singular structure, two RRM RNA-binding domains, and a long disordered C-terminal region which plays roles in functional RNA regulatory assemblies as well as pernicious aggregation. Evidence from pathological mutations and seeding experiments strongly suggest that TDP-43 aggregates are pathologically relevant through toxic gain-of-harmful-function and/or harmful loss-of-native-function mechanisms. Recent, but not early, microscopy studies and the ability of TDP-43 aggregates to resist harsh treatment and to seed new pathological aggregates in vitro and in cells strongly suggest that TDP-43 aggregates have a self-templating, amyloid-like structure. Based on the importance of the Gln/Asn-rich 341–367 residue segment for efficient aggregation of endogenous TDP-43 when presented as a 12X-repeat and extensive spectroscopic and computational experiments, we recently proposed that this segment adopts a beta-hairpin structure that assembles in a parallel with a beta-turn configuration to form an amyloid-like structure. Here, we propose that this conformer is stabilized by an especially strong class of hypercooperative hydrogen bonding unique to Gln and Asn sidechains. The clinical existence of this conformer is supported by very recent LC-MS/MS characterization of TDP-43 from ex vivo aggregates, which show that residues 341–367 were protected in vivo from Ser phosphorylation, Gln/Asn deamidation and Met oxidation. Its distinct pattern of SDS-PAGE bands allows us to link this conformer to the exceptionally stable seed of the Type A TDP-43 proteinopathy.

show abstract

Section: Introductionsupporting

confidence: 54%

“…In contrast, several studies found that short peptides derived from TDP-43’s second RRM domain and C-terminal region adopt fibril structures that bind amyloid-specific dyes (Chen et al, 2010; Guo et al, 2011; Saini and Chauhan, 2011, 2014; Jiang et al, 2013; Mompeán et al, 2014; Sun et al, 2014; Zhu et al, 2014). …”

Section: Introductionmentioning

confidence: 98%

An Amyloid-Like Pathological Conformation of TDP-43 Is Stabilized by Hypercooperative Hydrogen Bonds

Mompeán

Baralle

Buratti

et al. 2016

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…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. 42 ).…”

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

110

View full text Add to dashboard Cite

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.

show abstract

“…Consequently, a number of studies have focused on the aggregation propensity of TDP-43 in the context of disease mutations (Budini et al, 2012; Jiang et al, 2013; Mompean et al, 2014), although the effects of TDP-43 aggregates on the severity of the disease phenotype in vivo are unclear(Ash et al, 2010; D'Alton et al, 2014; Estes et al, 2011). Here, we demonstrate here that the tested ALS-causing mutations result in perturbations to liquid phase separation via alteration of interactions of a uniquely well-conserved segment of the C-terminal domain.…”

Section: Discussionmentioning

confidence: 99%

ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain

et al. 2016

View full text Add to dashboard Cite

Summary RNA-binding protein TDP-43 mediates essential RNA processing but forms cytoplasmic neuronal inclusions via its C-terminal domain (CTD) in amyotrophic lateral sclerosis (ALS). It remains unclear if aggregated TDP-43 is neurotoxic and if ~50 ALS-associated missense mutations in TDP-43 CTD promote aggregation, or if loss-of-normal-function plays a role in disease. Recent work points to the ability of related proteins to assemble into functional phase-separated ribonucleoprotein granules via their structurally-disordered “prion-like” domains. Here, we provide atomic details on the structure and assembly of the low-complexity CTD of TDP-43 into liquid-liquid phase-separated in vitro granules and demonstrate that ALS-associated variants disrupt interactions within granules. Using NMR spectroscopy, simulation, and microscopy, we find that a subregion cooperatively but transiently folds into a helix that mediates TDP-43 phase separation. ALS-associated mutations disrupt phase separation by inhibiting interaction and helical stabilization. Therefore, ALS-associated mutations can disrupt TDP-43 interactions, affecting function beyond encouraging aggregation.

show abstract

“Structural characterization of the minimal segment of TDP-43 competent for aggregation”

Cited by 69 publications

References 43 publications

An Amyloid-Like Pathological Conformation of TDP-43 Is Stabilized by Hypercooperative Hydrogen Bonds

An Amyloid-Like Pathological Conformation of TDP-43 Is Stabilized by Hypercooperative Hydrogen Bonds

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

ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain

Contact Info

Product

Resources

About