Altered Thiol Chemistry in Human Amyotrophic Lateral Sclerosis-linked Mutants of Superoxide Dismutase 1

Solsona, Carles; Kahn, Thomas B.; Badilla, Carmen L.; Álvarez-Zaldiernas, Cristina; Blasi, Juan; Fernández, Julio M.; Alegre-Cebollada, Jorge

doi:10.1074/jbc.m114.565333

Cited by 16 publications

(14 citation statements)

References 66 publications

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“…5) (45). Although Cys 111 is not the only residue to mediate misfolding/aggregation, it is the only Cys residue present in SOD1 from primates, and its role in ALS pathophysiology has been considered (28,45). Because of its location in the surface of the protein, Cys 111 may interact with Cys 57 or Cys 146 and reorganize the intramolecular disulfide bond (20) and would reorient the Cu 2ϩ .…”

Section: Discussionmentioning

confidence: 99%

“…9, which also shows how the Trx and GSH-Grx systems participate in this process. Mutation in hSOD1 dimers exposes its conserved Cys 57 -Cys 146 disulfide on the protein surface in either one or both subunits (28,29), where it is easy to be reduced by the Trx and Grx systems into dithiol form, followed by the dimer dissociation. We can also find non-conserved disulfide bond forms, as Cys 6 -Cys 111 and Cys 146 -Cys 111 in SOD1 dimers, that are in a balance because of the Trx-GSH/ Grx redox systems.…”

Section: Discussionmentioning

confidence: 99%

“…The reactivity of Cys 111 toward the conserved disulfide bond in WT and G93A or A4V mutant SOD1 is different (28). Our aim here is to investigate the effects of the Trx and Grx systems on the redox state of wild-type and G93A and A4V mutant hSOD1 to evaluate the contribution of cellular redox environment change to SOD1 aggregation and ALS progression.…”

mentioning

confidence: 99%

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Cellular Redox Systems Impact the Aggregation of Cu,Zn Superoxide Dismutase Linked to Familial Amyotrophic Lateral Sclerosis

Álvarez-Zaldiernas

Zheng

et al. 2016

Journal of Biological Chemistry

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Protein misfolding is implicated in neurodegenerative diseases such as ALS, where mutations of superoxide dismutase 1 (SOD1) account for about 20% of the inherited mutations. Human SOD1 (hSOD1) contains four cysteines, including Cys 57 and Cys 146 , which have been linked to protein stability and folding via forming a disulfide bond, and Cys 6 and Cys 111 as free thiols. But the roles of the cellular oxidation-reduction (redox) environment in SOD1 folding and aggregation are not well understood. Here we explore the effects of cellular redox systems on the aggregation of hSOD1 proteins. We found that the known hSOD1 mutations G93A and A4V increased the capability of the thioredoxin and glutaredoxin systems to reduce hSOD1 compared with wild-type hSOD1. Treatment with inhibitors of these redox systems resulted in an increase of hSOD1 aggregates in the cytoplasm of cells transfected with mutants but not in cells transfected with wild-type hSOD1 or those containing a secondary C111G mutation. This aggregation may be coupled to changes in the redox state of the G93A and A4V mutants upon mild oxidative stress. These results strongly suggest that the thioredoxin and glutaredoxin systems are the key regulators for hSOD1 aggregation and may play critical roles in the pathogenesis of ALS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Cellular Redox Systems Impact the Aggregation of Cu,Zn Superoxide Dismutase Linked to Familial Amyotrophic Lateral Sclerosis

Álvarez-Zaldiernas

Zheng

et al. 2016

Journal of Biological Chemistry

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“…cystine), and the factors that control this, are less well characterized, despite the critical importance of such bonds in maintaining protein structures. Disulfide bond modification is postulated to be a key factor in determining the shelf life and activity of protein- and peptide-based medicines including antibodies and vaccines2122, in food processing and spoilage23, in amyloid and aggregate formation2425 and in some human diseases2627.…”

mentioning

confidence: 99%

Reactivity of disulfide bonds is markedly affected by structure and environment: implications for protein modification and stability

Karimi

Ignasiak

Chan

et al. 2016

Sci Rep

122

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Disulfide bonds play a key role in stabilizing protein structures, with disruption strongly associated with loss of protein function and activity. Previous data have suggested that disulfides show only modest reactivity with oxidants. In the current study, we report kinetic data indicating that selected disulfides react extremely rapidly, with a variation of 104 in rate constants. Five-membered ring disulfides are particularly reactive compared with acyclic (linear) disulfides or six-membered rings. Particular disulfides in proteins also show enhanced reactivity. This variation occurs with multiple oxidants and is shown to arise from favorable electrostatic stabilization of the incipient positive charge on the sulfur reaction center by remote groups, or by the neighboring sulfur for conformations in which the orbitals are suitably aligned. Controlling these factors should allow the design of efficient scavengers and high-stability proteins. These data are consistent with selective oxidative damage to particular disulfides, including those in some proteins.

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“…Solsona et al found that two disease-causing mutations (G39A and A4v) alter the reactivity and disulfide bonding patterns of Sod1 using single-molecule force-clamp assays. 59 First, it was clear from single-disulfide cleavage experiments by TCep on wild-type Sod1 that the Cys57-Cys146 disulfide bond is buried, as cleavage occurred only after unfolding, generating a characteristic increase in protein length upon reduction. After unfolding, single isomerization events due to attack of Cys111 on the disulfide were observed.…”

Section: Disulfide Isomerization In Superoxide Dismutase 1 (Sod1)mentioning

confidence: 99%

CHAPTER 1.3. Real-time Detection of Thiol Chemistry in Single Proteins

Eckels¹,

Echelman²,

Rivas‐Pardo³

et al. 2018

Chemical Biology

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The cell is exquisitely tuned to alter its functions and gene expression in response to changes in its redox environment. Initiation of signaling pathways thus requires proteins that are sensitive to redox conditions, which is usually achieved through strategic placement of cysteine residues within the protein. A major challenge for protein biochemists studying these pathways is to detect changes in the redox status in one or several cysteine residues in a protein in a reliable and time-resolved manner. Many techniques used to detect the redox state of a particular amino acid require treatment of the protein samples with chemical probes that react with side-chains of a certain oxidation state. The probes do not always react with absolute specificity for the side-chains, and there is always concern that the redox state of the side-chains may change during the isolation and treatment process. Single-molecule force spectroscopy (SMFS) provides a means for executing ChApTer 1.3

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Altered Thiol Chemistry in Human Amyotrophic Lateral Sclerosis-linked Mutants of Superoxide Dismutase 1

Cited by 16 publications

References 66 publications

Cellular Redox Systems Impact the Aggregation of Cu,Zn Superoxide Dismutase Linked to Familial Amyotrophic Lateral Sclerosis

Cellular Redox Systems Impact the Aggregation of Cu,Zn Superoxide Dismutase Linked to Familial Amyotrophic Lateral Sclerosis

Reactivity of disulfide bonds is markedly affected by structure and environment: implications for protein modification and stability

CHAPTER 1.3. Real-time Detection of Thiol Chemistry in Single Proteins

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