Accessibility explains preferred thiol-disulfide isomerization in a protein domain

Kolšek, Katra; Aponte-Santamaría, Camilo; Gräter, Frauke

doi:10.1038/s41598-017-07501-4

Cited by 34 publications

(41 citation statements)

References 53 publications

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“…Achieving a native disulfide pattern during folding, for proteins that contain more than two cysteine residues, often involves the reduction and rearrangement of non-native disulfide bonds. These must be surface-exposed in order to be accessible to attacking thiols during isomerisation [ 73 , 74 ]. It is well established that reducing PDIs act on released substrates in the ER; however, can they also act on substrates at the co-translational stage?…”

Section: The Role Of Pdi Family Members In Nascent Polypeptide Folmentioning

confidence: 99%

Mechanisms of Disulfide Bond Formation in Nascent Polypeptides Entering the Secretory Pathway

Robinson

Bulleid

2020

Cells

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Disulfide bonds are an abundant feature of proteins across all domains of life that are important for structure, stability, and function. In eukaryotic cells, a major site of disulfide bond formation is the endoplasmic reticulum (ER). How cysteines correctly pair during polypeptide folding to form the native disulfide bond pattern is a complex problem that is not fully understood. In this paper, the evidence for different folding mechanisms involved in ER-localised disulfide bond formation is reviewed with emphasis on events that occur during ER entry. Disulfide formation in nascent polypeptides is discussed with focus on (i) its mechanistic relationship with conformational folding, (ii) evidence for its occurrence at the co-translational stage during ER entry, and (iii) the role of protein disulfide isomerase (PDI) family members. This review highlights the complex array of cellular processes that influence disulfide bond formation and identifies key questions that need to be addressed to further understand this fundamental process.

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Section: The Role Of Pdi Family Members In Nascent Polypeptide Folmentioning

confidence: 99%

Mechanisms of Disulfide Bond Formation in Nascent Polypeptides Entering the Secretory Pathway

Robinson

Bulleid

2020

Cells

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“…However, only in 2007, with the development of the exciting single-molecule techniques, were Julio Fernandez and co-workers (Wiita et al, 2006;Alegre-Cebollada et al, 2010), able to study the force-dependent chemical kinetics of the disulfide bond reduction, reporting a value of 0.34 Å, for the distance to the transition state of the reaction, in perfect agreement with Fernandes and Ramos work of 2004 (Fernandes and Ramos, 2004). More recently, Kolšek and co-workers suggested that thiol-disulfide exchange in protein folding often relies on simple accessibility criteria between thiolates (Kolsek et al, 2017).…”

Section: Introductionmentioning

confidence: 60%

Structural and mechanistic aspects of S-S bonds in the thioredoxin-like family of proteins

Sousa

Neves

Waheed

et al. 2018

Biological Chemistry

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Disulfide bonds play a critical role in a variety of structural and mechanistic processes associated with proteins inside the cells and in the extracellular environment. The thioredoxin family of proteins like thioredoxin (Trx), glutaredoxin (Grx) and protein disulfide isomerase, are involved in the formation, transfer or isomerization of disulfide bonds through a characteristic thiol-disulfide exchange reaction. Here, we review the structural and mechanistic determinants behind the thiol-disulfide exchange reactions for the different enzyme types within this family, rationalizing the known experimental data in light of the results from computational studies. The analysis sheds new atomic-level insight into the structural and mechanistic variations that characterize the different enzymes in the family, helping to explain the associated functional diversity. Furthermore, we review here a pattern of stabilization/destabilization of the conserved active-site cysteine residues presented beforehand, which is fully consistent with the observed roles played by the thioredoxin family of enzymes.

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“…Recent evidences suggest that disulphide bonds in proteins are highly dynamic (reviewed in [ 34 ]). Disulphide bonds may react with thiols within proteins even in the absence of enzymes and re-shuffle spontaneously or on an external stimulus, inducing changes in protein conformation and possibly function [ 3 , 22 ]. To examine this possibility, we performed homology modeling search for possible candidate cysteines.…”

Section: Resultsmentioning

confidence: 99%

Molecular basis for potentiation of Cx36 gap junction channel conductance by n-alcohols and general anesthetics

et al. 2018

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In our recent study, we have demonstrated that short carbon chain n-alcohols (up to octanol) stimulated while long carbon chain n-alcohols inhibited the conductance of connexin (Cx) 36 (Cx36) gap junction (GJ) channels. In contrast, GJ channels composed of other types of Cxs all were inhibited by n-alcohols independent of their carbon chain length. To identify the putative structural domains of Cx36, responsible for the dual effect of n-alcohols, we performed structural modeling of Cx36 protein docking with hexanol and isoflurane that stimulated as well as nonanol and carbenoxolone that inhibited the conductance of Cx36 GJs and revealed their multiple common docking sites and a single pocket accessible only to hexanol and isoflurane. The pocket is located in the vicinity of three unique cysteine residues, namely C264 in the fourth, and C92 and C87 in the second transmembrane domain of the neighboring Cx36 subunits. To examine the hypothesis that disulphide bonding might be involved in the stimulatory effect of hexanol and isoflurane, we generated cysteine substitutions in Cx36 and demonstrated by a dual whole-cell patch-clamp technique that in HeLa (human cervix carcinoma cell line) and N2A (mouse neuroblastoma cell line) cells these mutations reversed the stimulatory effect of hexanol and isoflurane to inhibitory one, typical of other Cxs that lack respective cysteines and a specific docking pocket for these compounds. Our findings suggest that the stimulatory effect of hexanol and isoflurane on Cx36 GJ conductance could be achieved by re-shuffling of the inter-subunit disulphide bond between C264 and C92 to the intra-subunit one between C264 and C87.

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Accessibility explains preferred thiol-disulfide isomerization in a protein domain

Cited by 34 publications

References 53 publications

Mechanisms of Disulfide Bond Formation in Nascent Polypeptides Entering the Secretory Pathway

Mechanisms of Disulfide Bond Formation in Nascent Polypeptides Entering the Secretory Pathway

Structural and mechanistic aspects of S-S bonds in the thioredoxin-like family of proteins

Molecular basis for potentiation of Cx36 gap junction channel conductance by n-alcohols and general anesthetics

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