Cysteine Function Governs Its Conservation and Degeneration and Restricts Its Utilization on Protein Surfaces

Abstract

Cysteine (Cys) is an enigmatic amino acid residue. Although one of the least abundant, it often occurs in functional sites of proteins. Whereas free Cys is a polar amino acid, Cys in proteins is often buried and its classification on the hydrophobicity scale is ambiguous. We hypothesized that deviation of Cys residues from the properties of a free amino acid is due to their reactivity and addressed this possibility by examining Cys in large protein structure datasets. Compared to other amino acids, Cys was characterized by the most extreme conservation pattern, with the majority of Cys being either highly conserved or poorly conserved. In addition, clustering of Cys with another Cys residue was associated with high conservation, whereas exposure of Cys on protein surface with low conservation. Moreover, although clustered Cys behaved as polar residues, isolated Cys was the most buried residue of all, in disagreement with known physico-chemical properties of Cys. Thus, anomalous hydrophobic behavior and conservation pattern of Cys can be explained by elimination, during evolution, of isolated Cys from protein surface and clustering of other Cys residues. These findings indicate that Cys abundance is governed by Cys function in protein rather than by the sheer chemical and physical properties of the free amino acid, and suggest that high tendency of Cys to be functionally active can considerably limit its abundance on protein surface.