An Intrinsically Disordered Domain Has a Dual Function Coupled to Compartment-Dependent Redox Control

Banci, Lucia; Bertini, Ivano; Cefaro, Chiara; Ciofi‐Baffoni, Simone; Gajda, Karolina; Felli, Isabella C.; Gallo, Angelo; Pavelkova, Anna; Kallergi, Emmanouela; Andreadaki, Maria; Katrakili, Nitsa; Pozidis, Charalambos; Tokatlidis, Kostas

doi:10.1016/j.jmb.2012.11.032

Cited by 17 publications

(14 citation statements)

References 54 publications

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“…Without folded structures, IDPs/IDRs exist in an ensemble of rapidly‐changing conformations with a flat free‐energy landscape and exhibit almost unlimited structural heterogeneity . On the other hand, most IDPs/IDRs undergo a disorder‐to‐order transition upon binding to their biological partners (i.e., coupled folding and binding), although some remain disordered even in their bound state …”

Section: Introductionmentioning

confidence: 99%

Advantages of proteins being disordered

2014

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The past decade has witnessed great advances in our understanding of protein structure-function relationships in terms of the ubiquitous existence of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs). The structural disorder of IDPs/IDRs enables them to play essential functions that are complementary to those of ordered proteins. In addition, IDPs/IDRs are persistent in evolution. Therefore, they are expected to possess some advantages over ordered proteins. In this review, we summarize and survey nine possible advantages of IDPs/IDRs: economizing genome/protein resources, overcoming steric restrictions in binding, achieving high specificity with low affinity, increasing binding rate, facilitating posttranslational modifications, enabling flexible linkers, preventing aggregation, providing resistance to non-native conditions, and allowing compatibility with more available sequences. Some potential advantages of IDPs/IDRs are not well understood and require both experimental and theoretical approaches to decipher. The connection with protein design is also briefly discussed.

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Section: Introductionmentioning

confidence: 99%

Advantages of proteins being disordered

2014

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“…The reoxidation of the CPC motif is ensured by the FAD-linked sulfhydryl oxidase 83 Erv1 (human equivalent: ALR) [31][32][33]. This step is mediated specifically by the natively 84 disordered N-terminal segment of Erv1 [34] that contains a CX 2 C motif. The pair of electrons 85 that are released during the formation of the disulfide bond are subsequently transferred in a 86 cascade of reactions from the N-terminal CX 2 C motif of Erv1 (C30/C33) to its FAD-proximal 87 CX 2 C pair (C130/C133), onto the flavin moiety, and then to cytochrome c, cytochrome 88 oxidase (COX) and finally molecular oxygen.…”

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confidence: 99%

Mitochondrial Proteins Containing Coiled-Coil-Helix-Coiled-Coil-Helix (CHCH) Domains in Health and Disease

Modjtahedi

Tokatlidis

Dessen

et al. 2016

Trends in Biochemical Sciences

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Members of the coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein family that carry (CX 9 C) type motifs are imported into the mitochondrion with the help of the disulfide relay-dependent MIA import pathway. These evolutionary-conserved proteins are emerging as new cellular factors that control mitochondrial respiration, redox regulation, lipid homeostasis or membrane ultrastructure and dynamics. Here, we discuss recent insights on the activity of known (CX 9 C) motif-carrying proteins in mammals and review current data implicating the MIA40/CHCHD4 import machinery in the regulation of their mitochondrial import. Recent findings and the identification of disease-associated mutations in specific (CX 9 C) motif-carrying proteins have highlighted members of this family of proteins as potential therapeutic targets in a variety of human disorders.

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“…It is worth to mention that the domains containing the shuttle cysteine residues of Erv1 and ALR are not conserved and both are largely unstructured. A recent structural study has suggested that the shuttle cysteine residues of Erv1 and ALR have different structural and solvent exposal properties [42]. Although both shuttle cysteine residues of ALR are located in a flexible segment, Cys 33 of Erv1 seems to be part of a α-helical structure with Cys 30 unstructured and thus more solvent exposed [42].…”

Section: Resultsmentioning

confidence: 99%

“…A recent structural study has suggested that the shuttle cysteine residues of Erv1 and ALR have different structural and solvent exposal properties [42]. Although both shuttle cysteine residues of ALR are located in a flexible segment, Cys 33 of Erv1 seems to be part of a α-helical structure with Cys 30 unstructured and thus more solvent exposed [42]. This result is consistent with our observation that Cys 30 is more reactive than Cys 33 in forming intermolecular disulfide bond between Erv1–Erv1′ and with Mia40.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial thiol oxidase Erv1: both shuttle cysteine residues are required for its function with distinct roles

Ang

Zhang

Lodi

et al. 2014

Biochemical Journal

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Erv1 (essential for respiration and viability 1), is an essential component of the MIA (mitochondrial import and assembly) pathway, playing an important role in the oxidative folding of mitochondrial intermembrane space proteins. In the MIA pathway, Mia40, a thiol oxidoreductase with a CPC motif at its active site, oxidizes newly imported substrate proteins. Erv1 a FAD-dependent thiol oxidase, in turn reoxidizes Mia40 via its N-terminal Cys30–Cys33 shuttle disulfide. However, it is unclear how the two shuttle cysteine residues of Erv1 relay electrons from the Mia40 CPC motif to the Erv1 active-site Cys130–Cys133 disulfide. In the present study, using yeast genetic approaches we showed that both shuttle cysteine residues of Erv1 are required for cell growth. In organelle and in vitro studies confirmed that both shuttle cysteine residues were indeed required for import of MIA pathway substrates and Erv1 enzyme function to oxidize Mia40. Furthermore, our results revealed that the two shuttle cysteine residues of Erv1 are functionally distinct. Although Cys33 is essential for forming the intermediate disulfide Cys33–Cys130′ and transferring electrons to the redox active-site directly, Cys30 plays two important roles: (i) dominantly interacts and receives electrons from the Mia40 CPC motif; and (ii) resolves the Erv1 Cys33–Cys130 intermediate disulfide. Taken together, we conclude that both shuttle cysteine residues are required for Erv1 function, and play complementary, but distinct, roles to ensure rapid turnover of active Erv1.

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An Intrinsically Disordered Domain Has a Dual Function Coupled to Compartment-Dependent Redox Control

Cited by 17 publications

References 54 publications

Advantages of proteins being disordered

Advantages of proteins being disordered

Mitochondrial Proteins Containing Coiled-Coil-Helix-Coiled-Coil-Helix (CHCH) Domains in Health and Disease

Mitochondrial thiol oxidase Erv1: both shuttle cysteine residues are required for its function with distinct roles

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