Evolution

Divergent Evolution and Protein Structure

The primary events in the development of biological diversity are the mutation, insertion, and deletion of nucleotides in DNA.

The primary structure of a protein is determined by the gene (DNA) that encodes it. A change in the gene may produce:

an alternative protein of equivalent function - a neutral mutation
a protein that carries out the same function, but with an altered rate or specificity
a protein with an altered function
a disfunctional protein, which may not even fold at all

That is, evolution of protein structures, in parallel with evolution of the organisms, may occur through positive or negative selection, or by fixation of random neutral variations.

Patterns of conservation or variation at individual positions provide clues to selective constraints: constraints that maintain or improve function.

Consider myoglobin, the oxygen storage protein. Here are the sequences from two myoglobins - that from a whale and one from a plant, lupin (the whale is on top) :

Sequence Alignment: Whale and Lupin Myoglobins

Not a lot of residues are conserved (25%) - that is, the same - between these two organisms, which diverged from a common ancestor some hundreds of millions of years ago.

Many of the differences are conservative in the sense of substituting one side chain for another of the same character

Residues crucial to functioning remain the same; for example, the His at position 100, which coordinates to the heme iron.

The result is two very similar forms, providing very similar function:

Sperm Whale Myoglobin	Lupin Leghemoglobin

Backbone Alignment of Whale (1mbd) and Lupin (2gdm) Globins
RMSD = 1.39 Å

Another example is insulin, synthesized initially as proinsulin, containing a sequence of residues that is excised to form the mature, functional hormone.

This "C chain" actually connects an "A chain" and a "B chain" that in the mature hormone are held together only by disulfide bonds (shown in yellow):

Human Insulin (1guj)

(The protein crystallizes as a dimer.)

We might expect, if we compare insulin from several species, to find that variation is greatest in the C chain, which is disfunctional, and conservation is greatest in the A and B chains, which are functional. Here is a table comparing the B and C chains of five species:

B Chain Sequences
Human	F	V	N	Q	H	L	C	G	S	H	L	V	E	A	L	Y	L	V	C	G	E	R	G	F	F	Y	T	P	K	T
Pig	F	V	N	Q	H	L	C	G	S	H	L	V	E	A	L	Y	L	V	C	G	E	R	G	F	F	Y	T	P	K	A
Cow	F	V	N	Q	H	L	C	G	S	H	L	V	E	A	L	Y	L	V	C	G	E	R	G	F	F	Y	T	P	K	A
Guinea Pig	F	V	S	R	H	L	C	G	S	N	L	V	E	T	L	Y	S	V	C	Q	D	D	G	F	F	Y	I	P	K	D
Rat	F	V	K	Q	H	L	C	G	P	H	L	V	E	A	L	Y	L	V	C	G	E	R	G	F	F	Y	T	P	K	S
C Chain Sequences
Human	R	R	E	A	E	D	L	Q	V	G	Q	V	E	L	G	G	G	P	G	A	G	S	L	Q	P	L	A	L	E	G	S	L	Q	K	R
Pig	R	R	E	A	E	N	P	Q	A	G	A	V	E	L	G	G	G	-	-	L	G	G	L	Q	A	L	A	L	E	G	P	P	Q	K	R
Cow	R	R	E	V	E	G	P	Q	V	G	A	L	E	L	A	G	G	P	G	A	G	G	L	-	-	-	-	-	E	G	P	P	Q	K	R
Guinea Pig	R	R	E	L	E	D	P	Q	V	E	Q	T	E	L	G	M	G	L	G	A	G	G	L	Q	P	L	A	L	E	M	A	L	Q	K	R
Rat	R	R	E	V	E	D	P	Q	V	P	Q	L	E	L	G	G	G	P	E	A	G	D	L	Q	T	L	A	L	E	V	A	R	Q	K	R

Note the double basic residues at each end of the C chain (RR, Arg-Arg, and KR, Lys-Arg).

These are the signals for cleavage of the C peptide and remain invariant.
Variability in the rest of the chain clearly is greater than in the A.
The table also indicates why, until the recent cloning of the human gene for insulin, the insulin provided to diabetics was porcine insulin.
One one amino acid varies in the B chain, and there is no difference whatsoever in the A chain (not shown here).

This page last modified 2:26 PM on Tuesday March 30th, 2010.
Webmaster, Department of Chemistry, University of Maine, Orono, ME 04469