Wednesday, March 3, 2010

TrimCyp-Crazy Convergence

A few weeks ago I started a series on host restriction factors. So…the Trim5alpha one may have been just a little too technical, sorry about that, I get carried away some times. I am going to try to increase the awesome evolutionary insight to boring biochemistry ratio in this post.

So last time I mentioned that Trim5alpha was made up of two major units, the recognition domain (SPRY) and the effector domain (TRIM). TrimCyp is a protein where the recognition domain has been replaced with a cyclophilin domain. It is an entire cyclophilin A molecule stuck to the TRIM part. Once HIV-1 gets into a cell it binds to cyclophilin A proteins. The cool part is that HIV actually needs cyclophilins to achieve maximum infectivity. So here we have a case where evolution has taken one of the things a virus like HIV-1 needs and fused it to the thing that helps chew HIV up…genius right! You can’t create a better thing. So how did it get there? A cyclophilin mRNA got picked up by some retrotransposition machinery and inserted it right in the Trim5a locus on the chromosome, poly A tail and all. A few splice site mutations sealed the deal for making a potent new restriction factor. Events like this are quite rare and the fact that it was maintained and selected for is pretty cool.

The really wild part of the story is the fact that it has happened twice independently.....on two different sides of the two totally different species. Talk about convergent evolution. It happened once in South America in owl monkeys and it probably did a good job because all 12 species of owl monkey only have this variant. Who knows maybe it saved the species. The second example is in macaques where it is distributed at different frequencies in at least 3 species ranging from about 10-100% . Again one would like to think this protein must have kicked some ancient viral ass. We know they were independent based on where they inserted into the genomic DNA, the macaque insertion is after the SPRY domain while the Owl monkey one comes before it.

If it is one thing evolution likes to do it is improve upon a good idea. It turns out mutating amino acids near the part that binds to HIV-1 changes its specificity for viruses. In the macaque protein these changes cause the loss of recognition for HIV-1 but the gain of recognition for HIV-2. That is a neat trick. Recent work actually shows that this switch is controlled by a singe amino acid change. One could imagine scenarios where at a population level the protein could flip flop specificities fairly quickly in response to new significant threats. There is a similar pattern of changes in the owl monkey version but no one has attributed any functional differences to it.

Personally I think the coolest part of the whole story is where the in the mutations in macaque and owl monkey proteins fall. The mutations that likely change binding specificity occurred just opposite each other! That was a WOW moment for me. These two species probably were faced with similar threats, solved the problem independently in a similar yet distinctly unique way!

I took this image of human cyclophilin A (same sequence as the macaque one) (PDB C3YS) colored it in PyMOL. Light blue is The cyclophilin A protein. The yellow ring is a drug cyclosporine that is bound to the active site, this is where it also binds to HIV. I colored the changes from human sequence to owl monkey in red. The orange ones are the macaque changes. Think of cyclophilin holding that ring like a whole hand gripping a ball. If you were to hold a ball in your hand and look down at it, the mutations in the owl monkey protein would be in the thumb and the macaque ones on the pinky. If you were to mutate “move” either finger you would change the grip on the ball. How cool is that?? I love evolution.

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