Histidine


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Standard codons for H : CAC CAT

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

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

Extracellular proteins:
Favoured
Neutral Ala ( 0) Pro ( 0) Asn ( 0) Asp ( 0) Glu ( 0) Gly ( 0) Lys ( 0) Gln ( 0)
Arg ( 0) Ser ( 0) Thr ( 0) Tyr ( 0)
Disfavoured Ile (-1) Met (-1) Leu (-1) Val (-1) Trp (-1) Phe (-1) Cys (-5)

Membrane proteins:
Favoured Gln ( 7) Tyr ( 6) Arg ( 5) Lys ( 4) Asp ( 3) Asn ( 3) Glu ( 2)
Disfavoured Trp (-1) Cys (-1) Ser (-2) Thr (-2) Phe (-3) Ala (-3) Gly (-3) Met (-3)
Ile (-4) Pro (-4) Leu (-4) Val (-4)


Substitutions: Histidine is a generally considered to be a polar amino acid, however it is quite unique with regard to properties, meaning that it does not particularly substitute well with any other amino acid (see above).

Role in structure: Histidine has a pKa near to that of physiological pH, meaning that it is relatively easy to move protons on and off of the side chain (i.e. changine the side chain from neutral to postive charge). This flexibility has two effects. The first is that it means Histidines is rather ambiguous about whether it prefers to be buried in the protein core, or exposed to solvent. The second is that it is an ideal residue for protein functional centres (discussed below).

Role in function: Histidines are the most common amino acids in protein active or binding sites. They are very common in metal binding sites (e.g. zinc), often acting together with Cysteines or other amino acids:

Thus in this context, it is common to see Histidine replaced by Cysteine.

The ease with which protons can be transfered on and off of Histidines makes them ideal for charge relay systems such as those found within catalytic triads, found in many Cysteine and Serine proteases:

In this context, it is quite rare to see Histidine exchange for any amino acid at all.


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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.
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