Finding S-sulfinylated proteins

Doerr, Allison

doi:10.1038/s41592-018-0200-2

Cited by 3 publications

(4 citation statements)

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“…However, this characterization of states is not optimal; many states are kinetically indistinguishable and interconvert rapidly (SI Figure 2). Hence, following previous work, 46 we processed the ensemble of trajectories using standard Markov state modeling software 21,46,47 as well as our own approach. 48,49 We featurized MELD trajectories in terms of the phi and psi dihedrals of each internal residue and projected them onto the principal components (tICA and dPCA+, 49 see SI Figure 3 for projections of principal components).…”

Section: Meld Samples the Relevant States And Populations Wellmentioning

confidence: 99%

“…Transition probabilities between states are estimated from either long or many short independent MD trajectories. Also, methods to build MSMs from independent trajectories include adaptive sampling [21][22][23] (spawning simulations in regions of higher uncertainties) and adaptive seeding 24,25 for choosing good starting configurations (e.g., the FAST algorithm 26 ) for spawning short trajectories.…”

Section: Introductionmentioning

confidence: 99%

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MELD-Path Efficiently Computes Conformational Transitions, Including Multiple and Diverse Paths

Pérez

Sittel

Stock

et al. 2018

J. Chem. Theory Comput.

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The molecular actions of proteins occur along reaction coordinates. Current computer methods have limited ability to explore them. We describe a fast protocol called MELD-path that (1) efficiently samples relevant conformational states via MELD, an accelerator of Molecular Dynamics (MD), (2) seeds multiple short MD trajectories from MELD states, and then (3) constructs Markov State Models (MSM) that give the routes and kinetics. We tested the method against extensive (multi μs) MD simulations of the right-handed- to left-handed-helix transition of a 9-mer peptide of AIB, the symmetry of which allows us to establish convergence. MELD-path finds all the metastable states, their correct relative populations, and the full ensemble of routes, not just a single assumed route. For this transition, we find a very broad route structure. MELD-path is highly parallelizable and efficient, yielding the full route map in a few days of computation. We believe MELD-path could be a general and rapid way to explore mechanistic processes in biomolecules on the computer.

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Section: Meld Samples the Relevant States And Populations Wellmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MELD-Path Efficiently Computes Conformational Transitions, Including Multiple and Diverse Paths

Pérez

Sittel

Stock

et al. 2018

J. Chem. Theory Comput.

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“…It was reported that 5% of the hepatic cysteines in the rat are present as SO 2 H. 162 S-sulfinylation is an elusive modification, and the identification depends on chemical probes, electrophilic probes and mass spectrum. 163 …”

Section: Principles and Mechanisms Of Protein Posttranslational Modif...mentioning

confidence: 99%

Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies

Geng

et al. 2023

Sig Transduct Target Ther

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The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. The most common form of NCD is metabolic diseases, which affect people of all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding of the pathobiology of metabolic diseases will generate novel targets for improved therapies across the common metabolic spectrum. Protein posttranslational modification (PTM) is an important term that refers to biochemical modification of specific amino acid residues in target proteins, which immensely increases the functional diversity of the proteome. The range of PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, and several novel PTMs. Here, we offer a comprehensive review of PTMs and their roles in common metabolic diseases and pathological consequences, including diabetes, obesity, fatty liver diseases, hyperlipidemia, and atherosclerosis. Building upon this framework, we afford a through description of proteins and pathways involved in metabolic diseases by focusing on PTM-based protein modifications, showcase the pharmaceutical intervention of PTMs in preclinical studies and clinical trials, and offer future perspectives. Fundamental research defining the mechanisms whereby PTMs of proteins regulate metabolic diseases will open new avenues for therapeutic intervention.

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“…the formation of mixed disulfide bonds between small thiol‐containing compounds and protein cysteinyl thiol groups. Within the field of oxidative stress, mass spectrometry has been used to detect protein thiol oxidations such as to sulfenic acid, 20–23 sulfinic acid, 24 sulfonic acid, 25–27 S‐thiolation by coenzyme A, 28 hydrogen sulfide, 29 cysteine perthiosulfenic acid, 30 S‐nitrosylation, 31–34 cysteine 35,36 and glutathionylation, 37–40 and to a lesser extent protein S‐thiolation by HcySH 41,42 …”

Section: Introductionmentioning

confidence: 99%

Investigating protein thiol chemistry associated with dehydroascorbate, homocysteine and glutathione using mass spectrometry

Ahuie

Gagnon

Pace

et al. 2020

Rapid Comm Mass Spectrometry

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Rationale:Oxidative stress is an imbalance between reactive free radical oxygen species and antioxidant defenses. Its consequences can lead to numerous pathologies. Regulating oxidative stress is the complex interplay between antioxidant recycling and thiol-containing regulatory proteins. Understanding these regulatory mechanisms is important for preventing onset of oxidative stress. The aim of this study was to investigate S-thiol protein chemistry associated with oxidized vitamin C (dehydroascorbate, DHA), homocysteine (HcySH) and glutathione (GSH) using mass spectrometry. Methods:Glutaredoxin-1 (Grx-1) was incubated with DHA, with and without GSH and HcySH. Disulfide formation was followed by electrospray ionization mass spectrometry (ESI-MS) of intact proteins and by LC/ESI-MS/MS of peptides from protein tryptic digestions. The mechanism of DHA-mediated S-thiolation was investigated using two synthetic peptides: AcFHACAAK and AcFHACE. Three proteins, i.e. human hemoglobin (HHb), recombinant peroxiredoxin 2 (Prdx2) andGrx-1, were S-homocysteinylated followed by S-transthiolyation with GSH and investigated by ESI-MS and ESI-MS/MS. Results: ESI-MS analysis reveals that DHA mediates disulfide formation andS-thiolation by HcySH as well as GSH of Grx-1. LC/ESI-MS/MS analysis allows identification of Grx-1 S-thiolated cysteine adducts. The mechanism by which DHA mediates S-thiolation of heptapeptide AcFHACAAK is shown to be via initial formation of a thiohemiketal adduct. In addition, ESI-MS of intact proteins shows that GSH can S-transthiolate S-homocysteinylated Grx-1, HHb and Prdx2.The GS-S-protein adducts over time dominate the ESI-MS spectrum profile. Conclusions:Mass spectrometry is a unique analytical technique for probing complex reaction mechanisms associated with oxidative stress. Using model proteins, ESI-MS reveals the mechanism of DHA-facilitated S-thiolation, which consists of thiohemiketal formation, disulfide formation or S-thiolation. Furthermore, protein S-thiolation by HcySH can be reversed by reversible GSH thiol exchange. The use of mass spectrometry with in vitro models of protein S-thiolation in oxidative stress may provide significant insight into possible mechanisms of action occurring in vivo.

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Finding S-sulfinylated proteins

Cited by 3 publications

References 0 publications

MELD-Path Efficiently Computes Conformational Transitions, Including Multiple and Diverse Paths

MELD-Path Efficiently Computes Conformational Transitions, Including Multiple and Diverse Paths

Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies

Investigating protein thiol chemistry associated with dehydroascorbate, homocysteine and glutathione using mass spectrometry

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