You only live twice

  • May 5, 2015
You only live twice

MAD FAIL. This is exactly what the protein I study spelled out for me. Proteins are a bit like a bracelet of pearls; each pearl (also known as an amino acid) is commonly named by one letter, A for alanine, L for leucine, and so forth… And this is how, hidden in my protein’s sequence, I discovered those two, somehow prophetic, words. MAD FAIL.

But let me explain in greater detail this delightful story of Nature’s twisted sense of humour. Oh yes, it gets better! The protein I study is called P2X7. P2X7, the James Bond of the cell, like any true secret agent, protects its secrets well. And as you may have guessed from my introduction, the chimera trap I set for my cellular James Bond was not quite as successful as expected. You see, in Biology, trying to study a little-known intracellular protein domain in which mutations lead to the degradation of the protein, is a bit like trying to observe deep-water giant squids with a snorkelling kit and a torch: it doesn’t quite work.

The one thing I learned with my chimeric James Bond, however, is that its function differs slightly across species. You would expect a British James Bond to speak English, and a French one to speak French (and smoke, eat bread and drink wine), right? Well, if you apply that to my cellular secret agent, it means that the rat P2X7 behaves differently to the human P2X7. I could also observe other differences between my chimeras and identify the P2X7 carboxyl tail as the carrier of the species differences. But then, what?

The aim of my chimera was to understand the order P2X7 needs to go on a mission, to meet the James Bond girls, but technical limitations (that would be the snorkelling kit) took those dreams away. So what information do the species differences provide? Where do they come from? Can I explain them? Who is James Bond?

To answer these questions, I looked at the protein sequences of each species (the pearl bracelet), and this is where I could see that the most conserved sequence of pearls was spelling out MAD FAIL. I think I first went into nervous laughter and could picture myself in one of those black and white movies when the hero thinks he’s finally about to catch the villain and all he finds is a small card reading “Sincerely yours”… I admit it drove me mad; million of years of evolution and the most conserved sequence of amino acids is there as a warning to anybody who dares to try and decipher P2X7's secrets. Seriously? How much more Hollywoodian could this PhD be?

Lost in all my questions, I then came across Theodosius Dobzhanski's thought that “nothing in Biology makes sense except in the light of evolution”. After all, even James Bond has a mother (#YouOnlyLiveTwice), so why not take advantage of the years of molecular evolution that have shaped today's agents in order to unravel their identity. Focusing on the P2X7 carboxyl tail, I used algorithms to draw a social profile of each of its pearls. As with a Facebook profile, I was able to identify likely friends, relationships and interests for amino acids of the P2X7 carboxyl tail with the aid of recently published studies. In more technical terms, I listed amino acids likely to be of importance for P2X7 function and its species differences, namely residues that either mutated more quickly than the rest of the protein (positively selected), mutated at the same time, communicated together and mutated independently but identically across species.

Every amino acid identified throughout this process has since yielded insights into P2X7's structure and function. We were able to strengthen the human P2X7 function (aka make the French James Bond eat fish and chips) and similarly to attenuate the rat P2X7 function (aka make the British James Bond eat frog's legs). Not only did the use of evolutionary studies allow me to better understand our cellular James Bond, it also provided insights into what drives its evolution. 

So, to answer the question who is the cellular James Bond, you may just have to read into its sequence and I am sure you will appreciate the fact that the final amino acids of human P2X7 spell the word SPY. True story. 

*Marie Brunet [2011] is doing a PhD in Pharmacology.

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