Proteomic approaches to quantify cysteine reversible modifications in aging and neurodegenerative diseases

Gu, Liqing; Robinson, Renã A. S.

doi:10.1002/prca.201600015

Cited by 33 publications

(30 citation statements)

References 170 publications

(273 reference statements)

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“…Reversible oxidative modifications, including S‐nitrosylation (Nakamura et al . ) and cysteine oxidation (Gu and Robinson ), may also provide insights into pathogenesis; however, the focus of this review is irreversible oxidative modifications associated with Aβ(1–42) indexed by protein carbonyls, HNE and 3‐NT as we summarize our current knowledge of Aβ(1–42)‐induced protein oxidation in vitro and in vivo as evidenced by redox proteomics. Here, we first highlight the proteins identified by redox proteomics as oxidatively modified in these models, relate these same proteins that also are oxidized in aMCI and AD brain, and then discuss the implications of such modifications in the context of our current knowledge of AD.…”

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confidence: 99%

Redox proteomics and amyloid β‐peptide: insights into Alzheimer disease

Butterfield

Boyd‐Kimball

2018

Journal of Neurochemistry

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Alzheimer disease (AD) is a progressive neurodegenerative disorder associated with aging and characterized pathologically by the presence of senile plaques, neurofibrillary tangles, and neurite and synapse loss. Amyloid beta-peptide (1-42) [Aβ(1-42)], a major component of senile plaques, is neurotoxic and induces oxidative stress in vitro and in vivo. Redox proteomics has been used to identify proteins oxidatively modified by Aβ(1-42) in vitro and in vivo. In this review, we discuss these proteins in the context of those identified to be oxidatively modified in animal models of AD, and human studies including familial AD, pre-clinical AD (PCAD), mild cognitive impairment (MCI), early AD, late AD, Down syndrome (DS), and DS with AD (DS/AD). These redox proteomics studies indicate that Aβ(1-42)-mediated oxidative stress occurs early in AD pathogenesis and results in altered antioxidant and cellular detoxification defenses, decreased energy yielding metabolism and mitochondrial dysfunction, excitotoxicity, loss of synaptic plasticity and cell structure, neuroinflammation, impaired protein folding and degradation, and altered signal transduction. Improved access to biomarker imaging and the identification of lifestyle interventions or treatments to reduce Aβ production could be beneficial in preventing or delaying the progression of AD. This article is part of the Proteomics special issue.

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confidence: 99%

Redox proteomics and amyloid β‐peptide: insights into Alzheimer disease

Butterfield

Boyd‐Kimball

2018

Journal of Neurochemistry

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“…Misregulation of these post-translational modifications (PTMs) has been associated with hypertension, cancer, aging, and neurodegenerative diseases. 4–7 Thus, developing analytical techniques to profile these modifications is imperative.…”

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confidence: 99%

“…10,22 For oxidative-based cysteine modifications specifically, the recent development of chemical proteomics methods has greatly advanced our understanding of redox regulation. 7,23–25 The most widely used approach involves immediate alkylation of free cysteine residues, followed by the reduction and subsequent capture of any newly reduced cysteines. These methods are valuable for identifying proteins with redox-based modifications and have led to the discovery of many redox-regulated proteins and pathways.…”

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confidence: 99%

Targeted Annotation of S-Sulfonylated Peptides by Selective Infrared Multiphoton Dissociation Mass Spectrometry

et al. 2017

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Protein S-sulfinylation (R-SO2−) and S-sulfonylation (R-SO3−) are irreversible oxidative post-translational modifications of cysteine residues. Greater than 5% of cysteines are reported to occupy these higher oxidation states, which effectively inactivate the corresponding thiols and alter the electronic and physical properties of modified proteins. Such higher oxidation states are reached after excessive exposure to cellular oxidants, and accumulate across different disease states. Despite widespread and functionally relevant cysteine oxidation across the proteome, there are currently no robust methods to profile higher order cysteine oxidation. Traditional data-dependent liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods generally miss low occupancy modifications in complex analyses. Here, we present a data-independent acquisition (DIA) LC/MS-based approach, leveraging the high IR absorbance of sulfoxides at 10.6 μm, for selective dissociation and discovery of S-sulfonated peptides. Across peptide standards and protein digests, we demonstrate selective infrared multiphoton dissociation (IRMPD) of S-sulfonated peptides in the background of unmodified peptides. This selective DIA IRMPD LC/MS-based approach allows identification and annotation of S-sulfonated peptides across complex mixtures while providing sufficient sequence information to localize the modification site.

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“…A role for redox reactions and high levels of NO leading to ubiquitination and proteasomal degradation has been discussed 44 , as has proteosomal-mediated quality control of S-nitrosylated mitochondrial proteins 45 . Complicating factors in experimental analysis of any coupling between cysteine oxidations and protein degradation include their reversibility 46 , and the absence of a consensus ubiquitination sequence motif 47 . The data shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Features of reactive cysteines discovered through computation: from kinase inhibition to enrichment around protein degrons

Fowler

Blanford

Visser

et al. 2017

Sci Rep

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Large-scale characterisation of cysteine modification is enabling study of the physicochemical determinants of reactivity. We find that location of cysteine at the amino terminus of an α-helix, associated with activity in thioredoxins, is under-represented in human protein structures, perhaps indicative of selection against background reactivity. An amino-terminal helix location underpins the covalent linkage for one class of kinase inhibitors. Cysteine targets for S-palmitoylation, S-glutathionylation, and S-nitrosylation show little correlation with pKa values predicted from structures, although flanking sequences of S-palmitoylated sites are enriched in positively-charged amino acids, which could facilitate palmitoyl group transfer to substrate cysteine. A surprisingly large fraction of modified sites, across the three modifications, would be buried in native protein structure. Furthermore, modified cysteines are (on average) closer to lysine ubiquitinations than are unmodified cysteines, indicating that cysteine redox biology could be associated with protein degradation and degron recognition.

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Proteomic approaches to quantify cysteine reversible modifications in aging and neurodegenerative diseases

Cited by 33 publications

References 170 publications

Redox proteomics and amyloid β‐peptide: insights into Alzheimer disease

Redox proteomics and amyloid β‐peptide: insights into Alzheimer disease

Targeted Annotation of S-Sulfonylated Peptides by Selective Infrared Multiphoton Dissociation Mass Spectrometry

Features of reactive cysteines discovered through computation: from kinase inhibition to enrichment around protein degrons

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