CysXXCys

CysXXCys, written as Cys-X-X-Cys, is a protein sequence motif in which two cysteine residues are separated by two unspecified amino acids. The X symbols denote any amino acid, so the motif can appear in various sequence contexts. This motif is a hallmark of redox-active proteins and of certain metal-binding domains, and it plays roles in catalysis, regulation, and metal coordination.

In redox biology, the CXXC motif forms a reversible disulfide bond during catalytic cycles. The thiol groups of the two cysteines can be protonated and deprotonated, enabling thiol-disulfide exchange with substrate proteins. A well-known example is thioredoxin, whose active site sequence is Cys-Gly-Pro-Cys (CGPC); this disulfide/thiol pair participates in the reduction of disulfide bonds in target proteins and is regenerated by thioredoxin reductase. CXXC motifs are found in a broad family of disulfide oxidoreductases, often functioning as the catalytic center for redox reactions.

The motif also participates in metal binding. Cysteine thiolates can coordinate metal ions such as zinc or participate in binding iron-sulfur clusters when arranged in suitable structural contexts. In such proteins, the CXXC pair contributes ligands that, together with other residues, establish the metal-binding geometry and redox properties necessary for function.

Context matters: not every occurrence of CXXC confers redox activity or metal binding. The functional role depends on the surrounding sequence, structural framework, and cellular environment. Overall, CysXXCys is a versatile motif that enables redox regulation and metal coordination across diverse proteins.