Abstract
Vicinal disulfides between sequence-adjacent cysteine residues are very rare and rather startling structural features which play a variety of functional roles. Typically discussed as an isolated curiosity, they have never received a general treatment covering both cis and trans forms. Enabled by the growing database of high-resolution structures, required deposition of diffraction data, and improved methods for discriminating reliable from dubious cases, we identify and describe distinct protein families with reliably genuine examples of cis or trans vicinal disulfides and discuss their conformations, conservation, and functions. No cis-trans interconversions and only one case of catalytic redox function are seen. Some vicinal disulfides are essential to large, functionally coupled motions, whereas most form the centers of tightly packed internal regions. Their most widespread biological role is providing a rigid hydrophobic contact surface under the undecorated side of a sugar or multiring ligand, contributing an important aspect of binding specificity.
Highlights
A disulfide bond between sequence-adjacent cysteines, known as a vicinal disulfide, is a very distinctive and interesting, but extremely rare, conformation
The vicinal disulfides studied here are the rare exceptions to all the above rules
The search results included three Cys-cis-Cys without the connecting disulfide at 2.6 to 3.9Å resolution (PDB ID: 2HTH, 4H65, and 4Q5Z), but for none of them was there close to adequate evidence that the peptide is cis
Summary
A disulfide bond between sequence-adjacent cysteines, known as a vicinal disulfide, is a very distinctive and interesting, but extremely rare, conformation. Adjacent Cys residues occur about as often as expected from single-Cys frequency 1, but are usually in the reduced form. Those SH groups typically point away from each other, and in general are not both seen to ligand the same metal ion 2, with an exception for mercury 3. When adjacent Cys do form disulfide bonds, the two bonds are nearly always to different partners 4, such as in the cystine knot motif of transcription factors 5 and toxins 6. The vicinal disulfides studied here are the rare exceptions to all the above rules.
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