Potential role of glutathione in evolution of thiol-based redox signaling sites in proteins.

Mohanasundaram, Kaavya A, Haworth, Naomi L, Grover, Mani P, Crowley, Tamsyn M, Goscinski, Andrzej and Wouters, Merridee A 2015, Potential role of glutathione in evolution of thiol-based redox signaling sites in proteins., Frontiers of pharmacology, vol. 6, pp. 1-15, doi: 10.3389/fphar.2015.00001.

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Title Potential role of glutathione in evolution of thiol-based redox signaling sites in proteins.
Author(s) Mohanasundaram, Kaavya A
Haworth, Naomi L
Grover, Mani P
Crowley, Tamsyn MORCID iD for Crowley, Tamsyn M orcid.org/0000-0002-3698-8917
Goscinski, Andrzej
Wouters, Merridee A
Journal name Frontiers of pharmacology
Volume number 6
Start page 1
End page 15
Total pages 15
Publisher Frontiers Media S. A.
Place of publication Lausanne, Switzerland
Publication date 2015-03-10
ISSN 1663-9812
Keyword(s) cross-strand disulfide
forbidden disulfide
redox-active disulfide
disulfide evolution
CD4 evolution
AKT evolution
post-translational cysteine modification
Summary Cysteine is susceptible to a variety of modifications by reactive oxygen and nitrogen oxide species, including glutathionylation; and when two cysteines are involved, disulfide formation. Glutathione-cysteine adducts may be removed from proteins by glutaredoxin, whereas disulfides may be reduced by thioredoxin. Glutaredoxin is homologous to the disulfide-reducing thioredoxin and shares similar binding modes of the protein substrate. The evolution of these systems is not well characterized. When a single Cys is present in a protein, conjugation of the redox buffer glutathione may induce conformational changes, resulting in a simple redox switch that effects a signaling cascade. If a second cysteine is introduced into the sequence, the potential for disulfide formation exists. In favorable protein contexts, a bistable redox switch may be formed. Because of glutaredoxin's similarities to thioredoxin, the mutated protein may be immediately exapted into the thioredoxin-dependent redox cycle upon addition of the second cysteine. Here we searched for examples of protein substrates where the number of redox-active cysteine residues has changed throughout evolution. We focused on cross-strand disulfides (CSDs), the most common type of forbidden disulfide. We searched for proteins where the CSD is present, absent and also found as a single cysteine in protein orthologs. Three different proteins were selected for detailed study-CD4, ERO1, and AKT. We created phylogenetic trees, examining when the CSD residues were mutated during protein evolution. We posit that the primordial cysteine is likely to be the cysteine of the CSD which undergoes nucleophilic attack by thioredoxin. Thus, a redox-active disulfide may be introduced into a protein structure by stepwise mutation of two residues in the native sequence to Cys. By extension, evolutionary acquisition of structural disulfides in proteins can potentially occur via transition through a redox-active disulfide state.
Language eng
DOI 10.3389/fphar.2015.00001
Field of Research 119999 Medical and Health Sciences not elsewhere classified
1115 Pharmacology And Pharmaceutical Sciences
Socio Economic Objective 929999 Health not elsewhere classified
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2015, Frontiers Media S. A.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30079065

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