Onset of disorder and protein aggregation due to oxidation-induced intermolecular disulfide bonds: case study of RRM2 domain from TDP-43

Rabdano, Sevastyan O.; Izmailov, Sergei A.; Luzik, Dmitrii; Groves, Adam; Podkorytov, Ivan S.; Skrynnikov, Nikolai R.

doi:10.1038/s41598-017-10574-w

Cited by 36 publications

(24 citation statements)

References 68 publications

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“…Cysteines are often important for catalytic activity or protein folding 31 . However, surface cysteines can also be involved in protein–protein aggregation and, in such cases, removing surface cysteines by mutagenesis can be helpful for experiments that require high protein concentrations 32 – 34 . Therefore, we chose to investigate the importance of cysteine residues present in hADAR1d.…”

Section: Resultsmentioning

confidence: 99%

High-throughput mutagenesis reveals unique structural features of human ADAR1

et al. 2020

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Adenosine Deaminases that act on RNA (ADARs) are enzymes that catalyze adenosine to inosine conversion in dsRNA, a common form of RNA editing. Mutations in the human ADAR1 gene are known to cause disease and recent studies have identified ADAR1 as a potential therapeutic target for a subset of cancers. However, efforts to define the mechanistic effects for disease associated ADAR1 mutations and the rational design of ADAR1 inhibitors are limited by a lack of structural information. Here, we describe the combination of high throughput mutagenesis screening studies, biochemical characterization and Rosetta-based structure modeling to identify unique features of ADAR1. Importantly, these studies reveal a previously unknown zinc-binding site on the surface of the ADAR1 deaminase domain which is important for ADAR1 editing activity. Furthermore, we present structural models that explain known properties of this enzyme and make predictions about the role of specific residues in a surface loop unique to ADAR1.

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Section: Resultsmentioning

confidence: 99%

High-throughput mutagenesis reveals unique structural features of human ADAR1

et al. 2020

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“…Structure-function analysis of the RRM1 domain has suggested that the cysteines (C-173 the C-175) in this domain, are crucial for the TDP-43's conformation and these are also involved in the pathogenic RRM1 self-assembly (Shodai et al, 2013). In another study, cysteines in the RRM2 domain (C-198 and C-244) could form self-aggregating disulfide-linked dimers upon oxidation and assembled into aggregated species (Rabdano et al, 2017). Notably, oxidation of the two N-terminal cysteines (C39 and C50) can contribute to oligomerization possibly by priming the process (seeding).…”

Section: Tdp-43 Pathology In Alsmentioning

confidence: 99%

Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis

Prasad

Bharathi

Sivalingam

et al. 2019

Front. Mol. Neurosci.

580

573

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TAR DNA binding protein 43 (TDP-43) is a versatile RNA/DNA binding protein involved in RNA-related metabolism. Hyper-phosphorylated and ubiquitinated TDP-43 deposits act as inclusion bodies in the brain and spinal cord of patients with the motor neuron diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While the majority of ALS cases (90–95%) are sporadic (sALS), among familial ALS cases 5–10% involve the inheritance of mutations in the TARDBP gene and the remaining (90–95%) are due to mutations in other genes such as: C9ORF72, SOD1, FUS , and NEK1 etc. Strikingly however, the majority of sporadic ALS patients (up to 97%) also contain the TDP-43 protein deposited in the neuronal inclusions, which suggests of its pivotal role in the ALS pathology. Thus, unraveling the molecular mechanisms of the TDP-43 pathology seems central to the ALS therapeutics, hence, we comprehensively review the current understanding of the TDP-43's pathology in ALS. We discuss the roles of TDP-43's mutations, its cytoplasmic mis-localization and aberrant post-translational modifications in ALS. Also, we evaluate TDP-43's amyloid-like in vitro aggregation, its physiological vs. pathological oligomerization in vivo , liquid-liquid phase separation (LLPS), and potential prion-like propagation propensity of the TDP-43 inclusions. Finally, we describe the various evolving TDP-43-induced toxicity mechanisms, such as the impairment of endocytosis and mitotoxicity etc. and also discuss the emerging strategies toward TDP-43 disaggregation and ALS therapeutics.

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“…RRM2 is unique in that it contains an additional β-strand (β4) that forms a number of intramolecular contacts when bound to RNA and intermolecular contacts in the absence of RNA ( 15 ). The β4-strand also forms part of a cryptic nuclear export signal that becomes exposed in C-terminal fragments (CTFs) following proteolytic cleavage resulting from pathological conditions, including oxidative stress ( 18 , 19 ), endoplasmic reticulum (ER) stress ( 20 , 21 ), thermal stress ( 22 ), loss of RNA binding ( 23 ), or acetylation ( 24 ). Numerous studies have shown that CTFs of TDP43 form toxic, insoluble, cytoplasmic aggregates in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) ( 16 , 23 , 25 – 30 ).…”

Section: Introductionmentioning

confidence: 99%