“Forbidden” Disulfides: Their Role as Redox Switches

Abstract

Seminal studies by Richardson and Thornton defined the constraints imposed by protein structure on disulfide formation and flagged forbidden regions of primary or secondary structure seemingly incapable of forming disulfide bonds between resident cysteine pairs. With respect to secondary structure, disulfide bonds were not found between cysteine pairs: A. on adjacent beta-stands; B. in a single helix or strand; C. on non-adjacent strands of the same beta-sheet. In primary structure, disulfide bonds were not found between cysteine pairs: D. adjacent in the sequence. In the intervening years it has become apparent that all these forbidden regions are indeed occupied by disulfide-bonded cysteines, albeit rather strained ones. It has been observed that sources of strain in a protein structure, such as residues in forbidden regions of the Ramachandran plot and cis-peptide bonds, are found in functionally important regions of the protein and warrant further investigation. Like the Ramachandran plot, the earlier studies by Richardson and Thornton have identified a fundamental truth in protein stereochemistry: "forbidden" disulfides adopt strained conformations, but there is likely a functional reason for this. Emerging evidence supports a role for forbidden disulfides in redox-regulation of proteins.

Structural and Functional Studies of Truncated Hemolysin A from Proteus mirabilis

“…CXXC motifs in other proteins have been shown to destabilize their structure and provide redox-dependent signaling and catalytic function (39). Based upon the far-UV-CD results, we propose an energetic argument to support the high conservation of cysteines 144 and 147 within the TpsA hemolysin family.…”

Unique Disulfide Bonds in Epidermal Growth Factor (EGF) Domains of β3 Affect Structure and Function of αIIbβ3 and αvβ3 Integrins in Different Manner

“…However, for some disulfides, an alternative functional role as redox switches that change the function of their resident protein when they are oxidized or reduced has been established. The functional disulfides are less stable and often form in "forbidden" regions of primary or secondary structures in which they put strain on the protein structure (27,28). There are two types of functional disulfides: catalytic and allosteric bonds (29).…”

Thiol–disulfide Homeostasis in Acute Appendicitis

“…Cysteine has a role in structural functions as well as exchanges of thioldisulfide in redox systems (18). Disulfides such as cysteines are members of redox systems such as thiol-disulphide exchanges (19).…”