Protein function, promiscuity, moonlighting and philosophy
I recently received an email from a graduate student in Philosophy regarding protein function. Not sure if that person wants his name advertised, so I will keep it to myself.
“I am a fan of your blog, and interested in the philosophy of biology. One particularly interesting question is what makes something have a function; when it comes to artifacts, we just check with whoever designed the thing. It gets more complicated when functions change, and things are used for purposes other than what they were originally designed for, but it’s still pretty straightforward. However, biological functions can’t go that route (unless maybe one is a fan of intelligent design). I’m curious what you think about this, after seeing you mention your interest in predicting the function of genes and proteins. Is the function of something just the causal role that it plays in some larger mechanism? Do you have to include evolutionary considerations? If you ever have the time, I’d love to hear your thoughts about this.”
Thanks very much
My rather rambling answer follows:
“Ouff, you’ve opened a pretty big can of worms, which many of us are having a problem with.
Function in biology is context dependent. An enzyme catalyzes a biochemical reaction, say, removing a phosphate molecule from a protein, However, by removing that phosphate from the protein, the enzyme changes something in the function of the cell, as phosphate molecules are the ‘signaling currency’ of the cell. So the enzyme fulfills a cellular function as well. Finally, suppose this cell is in a developing embryo, and the phosphate removal in this type of protein in many catalyzes the creation of a limb, or a particular organ or tissue: now we have a whole organismal functional context. Which one of those: the biochemical, cellular or organismal is the ‘real’ function of the cell? Well, obviously all three are ‘real’.
To add a twist, suppose that a this enzyme is also active in removing phosphates from proteins in the adult animal. Now the animal has reached maturity, and because of a mutation in one of the cells that enzyme does not work anymore. The intra-cellular signaling becomes defective and the protein accumulates in its ‘phosphorylated’ form. This signals a division of the cell, and suddenly you have a pre-cancerous situation. So from a health point of view, this mutant plays a role in the survival and proliferation of cancer cells. Interestingly, a protein that causes our spittle to froth (don’t try doing this around other people, gross), was first discovered as a nasopharenygeal cancer associated protein, and it is named as such. Many genes and proteins are named after they are found to do one thing, even though we generally associate them with something else, simply because of the context in which they were discovered.
Also, there are moonlighting proteins, which may simply perform different functions. A protein called APIS is part of the proteasome: a cellular protein shredder which is itself a rather large protein complex. APIS also plays a role in transcribing DNA to RNA: thus, it is part of a protein creation complex, and of a destruction complex. See this short paper on Moonlighting proteins.
Yes, evolutionary considerations always come in to play, it is the lens through which we examine all biological phenomena. Evolution does cause certain proteins to be ‘multi-purposed’, also, some types of protein structures are more amenable to a certain set of functions than others. Furthermore, certain proteins are ‘promiscuous‘: certain enzymes may work on more than a single substrate (“Promiscuous” is different from “moonlighting”, where enzymes do completely different jobs; being “promiscuous” means a single enzyme does the same thing, but with different partners: i.e. catalyze the destruction of a sugar, but with different types of sugar molecules). Promiscuous enzymes can clearly show a ‘trajectory of evolution’ i.e. going from being very specific for one substrate, to non-specific for several substrates (or vice-versa). Promiscuity is a good example of molecular adaptation and tradeoff: a promiscuous enzyme means you have a jack-of-all-trades in your genomic complement, and you have to spend less energy on controlling the production of several different enzymes for several different tasks. However, the flipside of having a jack of all trades is that he is the master of none: the catalysis reactions are generally less efficient, which may cause problems for the cell/organism.
Phew, I hope I managed to convey some of the complexities of this issue, and how we try to deal with them in a systematic fashion.
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Khersonsky O, Roodveldt C, & Tawfik DS (2006). Enzyme promiscuity: evolutionary and mechanistic aspects. Current opinion in chemical biology, 10 (5), 498-508 PMID: 16939713
Jeffery, C. (2003). Moonlighting proteins: old proteins learning new tricks Trends in Genetics, 19 (8), 415-417 DOI: 10.1016/S0168-9525(03)00167-7