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

Cysteine (Cys) is an enigmatic amino acid residue. Although one of the least abundant, it often occurs in the 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 t...

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Published in:Journal of molecular biology Vol. 404; no. 5; pp. 902 - 916
Main Authors: Marino, Stefano M., Gladyshev, Vadim N.
Format: Journal Article
Language:English
Published: Netherlands Elsevier Ltd 17.12.2010
Subjects:
amino acid conservation
Computational Biology - methods
Conserved Sequence
cysteine
Cysteine - chemistry
Cysteine - genetics
Cysteine - metabolism
exposure
Hydrophobic and Hydrophilic Interactions
hydrophobic scales
Protein Folding
Protein Structure, Tertiary
Proteins - chemistry
Proteins - genetics
Proteins - metabolism
reactive thiols
Sec
HH
exposure
cysteine
amino acid conservation
hydrophobic scales
QM
reactive thiols
PDB
ISSN:0022-2836, 1089-8638, 1089-8638
Online Access:Get full text
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Summary:Cysteine (Cys) is an enigmatic amino acid residue. Although one of the least abundant, it often occurs in the 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 the 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 data sets. 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 surfaces was associated with low conservation. Moreover, although clustered Cys behaved as polar residues, isolated Cys was the most buried residue of all, in disagreement with known chemical properties of Cys. Thus, the anomalous hydrophobic behavior and conservation pattern of Cys can be explained by elimination of isolated Cys from protein surfaces during evolution and by clustering of other Cys residues. These findings indicate that Cys abundance is governed by Cys function in proteins rather than by the sheer chemical–physical properties of free amino acids, and suggest that a high tendency of Cys to be functionally active can considerably limit its abundance on protein surfaces.
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ISSN:0022-2836
1089-8638
1089-8638
DOI:10.1016/j.jmb.2010.09.027