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Issue 46, 2013
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Between-strand disulfides: forbidden disulfides linking adjacent β-strands

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Between-strand disulfides (BSDs) connect cysteine (Cys) residues across adjacent strands of β-sheets. There are four BSD types which can be found in regular β-structure: CSDs, which link residues immediately opposite each other in the β-structure (residues i and j); ETDs, which connect Cys out of register by one residue (i and j ± 1); BDDs, which join Cys at positions i and j ± 2; and BFDs, which link residues i and j ± 3. Formation of these disulfides was initially predicted to be forbidden, producing too much local strain in the protein fold. However, BSDs do exist in nature. Significantly, their high levels of strain allow them to be involved in redox processes under physiological conditions. Here we characterise BSD motifs found in the Protein Data Bank (PDB), discussing important intrinsic factors, such as the disulfide conformation and torsional strain, and extrinsic factors, such as the influence of the β-sheet environment on the disulfide and vice versa. We also discuss the biological importance of BSDs, including the prevalence of non-homologous examples in the PDB, the conservation of BSD motifs amongst related proteins (BSD clusters) and experimental evidence for BSD redox activity. For clusters of homologous BSDs we present detailed data of the disulfide properties and the variations of these properties amongst the “redundant” structures. Identification of disulfides with the potential to be involved in biological redox processes via the analysis of these data will provide important insights into the function and mechanism of BSD-containing proteins. Characterisation of thiol-based redox signalling pathways will lead to significant breakthroughs in understanding the molecular basis of oxidative stress and associated pathways, such as ageing and neurodegenerative diseases.

Graphical abstract: Between-strand disulfides: forbidden disulfides linking adjacent β-strands

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Publication details

The article was received on 20 May 2013, accepted on 09 Aug 2013 and first published on 28 Oct 2013

Article type: Paper
DOI: 10.1039/C3RA42486C
Citation: RSC Adv., 2013,3, 24680-24705

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    Between-strand disulfides: forbidden disulfides linking adjacent β-strands

    N. L. Haworth and M. A. Wouters, RSC Adv., 2013, 3, 24680
    DOI: 10.1039/C3RA42486C

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