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Are there any examples of proteins that, without coming from a recent duplication event, underwent a mutation(s) that caused it to have a novel interaction with a new ligand, substrate, other protein or molecule? By novel I imply that it doesn’t revert to an ancestral interaction or develop an interaction that is already performed by a close relative. I imagine that such mutations would be extremely rare, and that duplication is almost always necessary to have them fixed in a lineage.

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  • $\begingroup$ Just to make sure I understand what you're saying... You're asking for an example of a protein which changed functions throughout generations without leaving a trace of the original protein or a paralog? $\endgroup$ – rotaredom Apr 25 at 18:31
  • $\begingroup$ I edited your question a little to remove some typos, but also edited your title. "Genuine" isn't required as you explain this in your quesion, and best to keep it short, but avoid abbreviations like aa — need to spell in full for indexing. $\endgroup$ – David Apr 25 at 22:00
  • $\begingroup$ Thank you. I meant a protein that acquired new interacting partners (ligands, proteins, etc) without being duplicated. Because I’m already aware of evidence of proteins acquiring new interacting partners by being first duplicated and while one of the copies maintained the original interactions the other acquired the new ones. $\endgroup$ – Marlo Apr 28 at 22:33
  • $\begingroup$ @Marlo, I have restructured my answer to address your question more directly and focus specifically on the AB polymorphism which does not involve gene duplication. Does this fit the bill? I don't quite understand the import of "an interaction that is already performed by a close relative". If the protein is distinct and original mutations occur in it independently, what relevence do the interactions performed by other proteins have? Is there some philosophical or other concern underlying your question? (Please include the @ handle in any reply — that way I'll be alerted.) $\endgroup$ – David Apr 29 at 12:41
  • $\begingroup$ I must say that I am disappointed that you have not responded to my last comment. You appeared to be keen to have an answer as I understand you also posted to SE Bioinformatics, and you can hardly deny that I took your question very seriously and have supplied an extensive, detailed and fully documented answer. I see that you have been a member of the SE community for over two years, so I would expect you to realize that it would be courteous to let me know whether or not the answer is what you require. $\endgroup$ – David May 7 at 15:52
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The polymorphism in the gene product of the human ABO locus seems to provide an example of what the question demands. It does not involve a gene duplication or recovery from loss of function; rather it involves changes that cause interactions with a different ligand, and the mutations that produce these changes have been identified and examined at a molecular level.

I have described the biochemistry of the human blood group system in an answer I gave to a previous question, so the cartoons of the reactions are reproduced from that answer. The diagrams of the molecular interactions and the gene cluster are new.

Human AB polymorphism

The products of the A and B alleles of the human ABO locus are glycosyltransferases:

AB blood group glycosyltransferases

One of the enzymes recognizes the sugar, galactose (activated by UTP), whereas the other recognizes N-acetylgalactosamine. There is no doubt that they are the products of different alleles of the same gene, even though this is a member of a gene cluster (see below).

The structures of both these enzymes have been determined and the differences of the interaction with their substrates at the active site modelled as shown below:

Glucosyl transferase active sites

There are four residues that differ critically between the two enzymes, three of which are shown. Two of these (Met/Leu 266 and Ala/Gly 268) make contact with the UDP-glucosyl substrates. The third (Ser/Gly 235) appears to affect the conformation of the H-antigen co-substrate.

How is a change in function possible without gene duplication?

The poster expresses the opinion (my rewording):

“I imagine that such mutations would be extremely rare, and that duplication is almost always necessary to have them fixed in a lineage.”

Why, then, is gene duplication not necessary in this case? The reason is that the enzymes involved are not indispensable: the product is an elaborated branched cell-surface polysaccharide, the function of which can be served by a range of variants. Indeed, the polysaccharide is functional without elaboration, as in the case of blood group ‘O’, where the enzyme is inactive. However, as discussed in my answer to the previous question, there may be a ‘hidden’ function that has driven the evolution of the polymorphism in humans. It has been suggested that the blood cell surface antigens were used by parasites such as the malarial parasite to enter the cells, and that variation provide resistance (albeit temporary, i.e. until the parasite evolved in response).

Footnote: Gene Clusters of Glucosylating enzymes

The question specifically asks for examples that do not come from a recent gene duplication. However I feel it important to mention the gene duplications that have produced such changes in the gene cluster to which the ABO locus belongs. This is to make it clear that the polymorphism is distinct from such examples.

Animals have the ability to vary the sugars on their cells by selecting from a large repertoire of genes with the potential to specify different glycosylating enzymes. An example is the GT6 gene family (glycosyltransferase family 6):

GT6 family enzymes

There are about seven members of this family, not all of which are present in every species. A paper by Turcot-Dubois et al. gives a detailed comparison of the genes in human, rat, toad and zebrafish. I just reproduce the gene map for the human cluster in which the four members of the family are indicated by solid triangles:

Human GT6 cluster

The enzymes specified by some of these gene have been characterized by X-ray crystallography, e.g. in this paper by Gastinel et al..

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