The
Significance of Sequence Conservation
Sequence Conservation is important
for 2 reasons:
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EVOLUTIONARY.
It makes sense that if closely related species are compared, their proteins
will be very similar .... in other words at most positions in the peptide
chain, the amino acids will be identical. This is called conservation.
Conversely, if the proteins from distantly related species are compared,
it would be expected that the proteins would be dissimilar ... in other
words the amino acid sequence would not be conserved. This
elementary logic implies that evolutionary divergence can be tracked by
analysis of protein similarities. The next section will show how evolutionary
"distance" is a direct correlate of conservation in the amino acid sequence
of proteins.
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FUNCTIONAL.
If an amino acid at a particular position plays a vital role in the function
of the protein, then any change in the amino acid would be expected to
decrease the function or even destroy it altogether. Thus any individual
which experienced a mutation to the gene, which changed the amino acid sequence
at this position, would probably exhibit an inferior phenotype. Thus, such
a mutation would be selected against through evolutionary time.
On the other hand, an amino acid
which was not important to the function of the protein might be changed
with little effect on function. Consequently an individual with a mutation
which changes an unimportant amino acid will not be selected against.
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on thumbnail to see full-size! |
The thumbnail shows an alignment
of b-globin from humans
and 10 other mammals. Among the positions at which amino acids are most
strongly conserved are:
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Glutamic Acid (E) at position 6.
-
Hisitidne (H) at position 63.
-
Histidine (H) at position 93.
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amino acids 62-68
-
amino acids 88-103 and 106-108
It might be hypothesized that these amino acids are important to function
because they have been conserved (changing them would impair function,
and would be selected against). |
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The conserved positions have been
mapped onto a graphic showing the secondary
and tertiary structure of human beta globin.
Recall that a critical component of a-globin,
b-globin
and myoglobin is the porphyrin
ring .... which binds iron ..... which binds oxygen. Now it makes
sense that the amino acids identified above were conserved!
Hisitidne (H) at position 63. |
pins the Fe atom in place within
the porphyrin ring from one side. |
Histidine (H) at position 92. |
pins the Fe atom in place from one
side. |
amino acids 62-68 |
forms one side of the binding pocket
into which the porphyrin ring is bound. |
amino acids 88-103 and 106-108 |
forms another side, and the bottom,
of the binding pocket. |
Glutamic Acid (E) at position 6. |
An anomaly! In sickle beta globin,
this hydrophilic amino acid is changed to hydrophobic valine. This causes
the hemoglobins to polymerize into long, stiff rods which distort the erythrocytes
into a sickled shape. |
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Of course, the mere fact that something makes sense, does
not make it true! Hypotheses such as this must still be confirmed by solving
the structure using X-ray crystallography. However hundreds of protein structures
have been solved, and they all show the absolute dependence of protein
function on molecular structure! |
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It is argued that conserved amino
acids have been conserved because changing them impairs the function of
the protein, so that the phenotype is selected against. It therefore follows
that an individual who carries such a mutation should have an abnormal
phenotype which makes them less healthy .... in other words a genetic disease!
The classic example is sickle
cell anemia.
However, as shown in the graphic to the left, there are many variants
of beta globin which have been discovered in people from all over the world.
It would be predicted that these people would not be completely healthy.
The actual clinical symptoms are described in OMIM.
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