A Primary Role for Disulfide Formation in the Productive Folding of Prokaryotic Cu,Zn-superoxide Dismutase

Sakurai, Yoshihiko; Anzai, Itsuki; Furukawa, Yoshiaki

doi:10.1074/jbc.m114.567677

Cited by 17 publications

(12 citation statements)

References 43 publications

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“…Therefore, ebselen likely reacts with one of the free Cys57 or Cys146 sulphydryls on SOD1, forming a transient selenyl-sulphide which is then easily rearranged by selenyl-thiol exchange to form the intra-subunit disulphide bond with the release of ebselen selenol. Disulphide bond formation greatly enhances the folding stability of mutant SOD1, an effect also observed for prokaryotic Cu/ZnSOD 49 , and improves zinc binding affinity. Thus, the level of soluble mutant protein, which is constituted by SOD1 not swiftly degraded or aggregated, is increased.…”

Section: Discussionmentioning

confidence: 68%

The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation

et al. 2018

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Superoxide dismutase-1 (SOD1) mutants, including those with unaltered enzymatic activity, are known to cause amyotrophic lateral sclerosis (ALS). Several destabilizing factors contribute to pathogenicity including a reduced ability to complete the normal maturation process which comprises folding, metal cofactor acquisition, intra-subunit disulphide bond formation and dimerization. Immature SOD1 forms toxic oligomers and characteristic large insoluble aggregates within motor system cells. Here we report that the cysteine-reactive molecule ebselen efficiently confers the SOD1 intra-subunit disulphide and directs correct SOD1 folding, depopulating the globally unfolded precursor associated with aggregation and toxicity. Assisted formation of the unusual SOD1 cytosolic disulphide bond could have potential therapeutic applications. In less reducing environments, ebselen forms a selenylsulphide with Cys111 and restores the monomer–dimer equilibrium of A4V SOD1 to wild-type. Ebselen is therefore a potent bifunctional pharmacological chaperone for SOD1 that combines properties of the SOD1 chaperone hCCS and the recently licenced antioxidant drug, edaravone.

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Section: Discussionmentioning

confidence: 68%

The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation

et al. 2018

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“…Some native structures were easier templates for optimization of secretability; such as Skp and Spy that have flexible native states (Burmann et al, 2013;Walton and Sousa, 2004; Figure S4) or the partially/completely disordered YebF and CsgA (Chapman et al, 2002;Prehna et al, 2012) (Figure 3B). Others remain unstructured/dynamic until they bind to stabilizing co-factors in the periplasm and fold (metals for SodC [Sakurai et al, 2014]; pentaheme for the c-type cytochrome NrfB [Clarke et al, 2007]; see apo-forms in Figure S4).…”

Section: Discussionmentioning

confidence: 99%

Long-Lived Folding Intermediates Predominate the Targeting-Competent Secretome

et al. 2018

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Secretory preproteins carry signal peptides fused amino-terminally to mature domains. They are post-translationally targeted to cross the plasma membrane in non-folded states with the help of translocases, and fold only at their final destinations. The mechanism of this process of postponed folding is unknown, but is generally attributed to signal peptides and chaperones. We herein demonstrate that, during targeting, most mature domains maintain loosely packed folding intermediates. These largely soluble states are signal peptide independent and essential for translocase recognition. These intermediates are promoted by mature domain features: residue composition, elevated disorder, and reduced hydrophobicity. Consequently, a mature domain folds slower than its cytoplasmic structural homolog. Some mature domains could not evolve stable, loose intermediates, and hence depend on signal peptides for slow folding to the detriment of solubility. These unique features of secretory proteins impact our understanding of protein trafficking, folding, and aggregation, and thus place them in a distinct class.

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“…Since the discovery of its association with ALS in 1993, more than 180 SOD1 mutations have been described (Pasinelli and Brown, 2006 ; Tripolszki et al, 2017 ). SOD1 encodes a ubiquitously expressed cytosolic enzyme with a molecular mass of 32 kDa (Nithya et al, 2016 ), and its normal cellular function is to detoxify the endogenously produced superoxide, by converting it to oxygen and hydrogen peroxide (Sakurai et al, 2014 ).…”

Section: Proteins Associated With Only Als or Ftdmentioning

confidence: 99%

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

Shahheydari

Ragagnin

Walker

et al. 2017

Front. Mol. Neurosci.

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Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that are now recognized to overlap clinically and pathologically, forming a continuous disease spectrum. In this review article, we detail the evidence for dysregulation of protein quality control mechanisms across the whole ALS-FTD continuum, by discussing the major proteins implicated in ALS and/or FTD. We also discuss possible ways in which protein quality mechanisms could be targeted therapeutically in these disorders and highlight promising protein quality control-based therapeutics for clinical trials.

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A Primary Role for Disulfide Formation in the Productive Folding of Prokaryotic Cu,Zn-superoxide Dismutase

Cited by 17 publications

References 43 publications

The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation

The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation

Long-Lived Folding Intermediates Predominate the Targeting-Competent Secretome

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

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