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spacer and the retinoic acid receptor a 5 bp spacer. Thus, both the sequence and the
spacing between the half-sites determines the specificity.
Most nuclear receptors have two or three amino acids (P box residues) in their
DNA-binding domains that serve to specify recognition of the response element
within the promoter of the target gene. Some residues (e.g. Val443 in the gluco-
corticoid receptor or Glu439 in the estrogen receptor) can contribute to specificity
both by forming a positive interaction with a base in the cognate response element
and by forming a negative interaction with a base in a noncognate response ele-
ment (Zilliacus et al ., 1994, 1995). In the glucocorticoid receptor, Ser440 inhibits
the interaction of the receptor with the ERE but at the cost of also reducing affin-
ity for the GRE (Zilliacus et al ., 1994, 1995). Thus, the diversification of steroid
receptor specificity was probably achieved during evolution by a relatively small
number of single base-pair substitutions either in the P-box encoding residues of
steroid receptors or in the response elements of their target genes.
The calcium-dependent and -independent synaptotagmins. Synaptotagmins
constitute a large family of proteins involved in membrane trafficking. At least
five different synaptotagmin genes have been characterized in the human genome
( SYT1 , 12cen-q21; SYT2 , 1q; SYT3 , 19q; SYT4 , 5q; SYT5 , 11p). Most synapto-
tagmins are capable of binding calcium through their calcium-binding C 2 A
domains. Synaptotagmins IV and XI are unique in their inability to bind calcium
and Von Poser et al. (1997) have shown that this inability is caused by the substi-
tution of Ser for Asp at residue 230 in the C 2 A domain. This substitution is evo-
lutionarily conserved in synaptotagmin IV and it seems likely that
synaptotagmins IV and XI shared a common ancestor in which the substitution
originated. Von Poser et al. (1997) postulated that evolution selected for the loss of
calcium binding in two different synaptotagmins while leaving the remainder of
the protein structures intact. This would of course imply that these synaptotag-
mins also possess calcium-independent properties and that these properties have
been retained by selection through evolutionary time.
Olfactory receptor-ligand interactions. Certain residues in the
-helical sixth
transmembrane domain of human olfactory receptors have been implicated in
interactions with their odorant ligands and these residues appear to have been
subject to positive selection (Singer et al. , 1996). The highly variable residues 6-22
and 6-25 are thought to constitute a receptor sub-site that binds hydroxyl groups
on odorant ligands; substitutions at these critical positions may therefore help to
determine the odor specificity of olfactory receptor sub-types. A Val/Ile difference
at residue 206 of the orthologous rat and mouse I7 olfactory receptor proteins has
been shown to be responsible for a species-specific odorant response; rats prefer-
ing octanal to heptanal, mice the reverse (Krautwurst et al. , 1998).
7.5.3 Single base-pair substitutions in evolution which have affected
mRNA splicing
Single base-pair substitutions affecting mRNA splicing make up between 8% and
15% of all mutations causing human genetic disease (Krawczak et al ., 1992). These
 
 
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