Standard codons for C : TGC TGT

Substitution preferences:
All protein types:
Neutral Ala ( 0)
Disfavoured Ile (-1) Val (-1) Met (-1) Leu (-1) Ser (-1) Thr (-1) Trp (-2) Phe (-2)
Tyr (-2) Gly (-3) His (-3) Lys (-3) Gln (-3) Arg (-3) Asn (-3) Pro (-3)
Asp (-3) Glu (-4)

Intracellular proteins:
Neutral Ala ( 0) Thr ( 0) Val ( 0) Phe ( 0) Tyr ( 0) His ( 0) Ile ( 0) Met ( 0)
Leu ( 0) Ser ( 0)
Disfavoured Lys (-1) Asn (-1) Gly (-1) Trp (-1) Arg (-1) Pro (-2) Asp (-2) Gln (-2)
Glu (-2)

Extracellular proteins:
Disfavoured Ala (-4) Tyr (-4) Val (-4) Thr (-5) Trp (-5) Phe (-5) His (-5) Ile (-5)
Leu (-5) Met (-5) Gln (-5) Arg (-5) Ser (-5) Gly (-6) Glu (-6) Pro (-6)
Lys (-6) Asn (-6) Asp (-7)

Membrane proteins:
Favoured Tyr ( 3) Ser ( 2) Phe ( 1) Trp ( 1)
Neutral Ala ( 0) Thr ( 0) Val ( 0)
Disfavoured Asn (-1) Gly (-1) His (-1) Arg (-1) Ile (-1) Leu (-1) Met (-1) Pro (-3)
Gln (-3) Lys (-3) Glu (-3) Asp (-3)

Substitutions: As can be seen above, Cysteine shows no preference generally for substituting with any other amino acid, though it can tolerate substitutions with other small amino acids. Largely the above preferences can be accounted for by the extremely varied roles that Cysteines play in proteins (see below). The substitutions preferences shown above are derived by analysis of all Cysteines, in all contexts, meaning that what are really quite varied preferences are averaged and blurred; the result being quite meaningless.

Role in structure: The role of Cysteines in structure is very dependent on the cellular location of the protein in which they are contained. Within extracellular proteins, cysteines are frequently involved in disulphide bonds, where pairs of cysteines are oxidised to form a covalent bond. These bonds serve mostly to stabilise the protein structure, and the structure of many extracellular proteins is almost entirely determined by the topology of multiple disulphide bonds (these are generally classified as small disulphide-rich proteins; and example is shown below).

The reducing environment inside cells makes the formation of disulphide bonds very unlikely. Indeed, instances of disulphide bonds in the intracellular environment are so rare that they almost always attract special attention. Disulphides are also rare within the membrane, though membrane proteins can contain disulphide bonds within extracellular domains.

In the intracellular environment Cysteines can still play a key structural role. Their sulfydryl side-chain is excellent for binding to metals, such as zinc, meaning the Cysteines (and other amino acids such as Histidines) are very common in metal binding motifs such as zinc fingers (below).

Outside of this context within the intracellular environment, and when it is not involved in molecular function, Cysteine is a neutral, small amino acid, and prefers to substitute with other amino acids of the same type.

Role in function: Cysteines are also very common in protein active and binding sites. Binding to metals (see above) can also be important in enzymatic functions (e.g. metal proteases). Cysteine can also function as a nucleophile (i.e. the reactive centre of an enzyme). Probably the best known example of this occurs within the Cysteine proteases, such as caspases, or papains (below), where Cysteine is the key catalytic residue, being helped by a Histidine and an Asparagine.

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Please cite: M.J. Betts, R.B. Russell. Amino acid properties and consequences of subsitutions.
In Bioinformatics for Geneticists, M.R. Barnes, I.C. Gray eds, Wiley, 2003.