Where did all the tyrosine go?

Proteins in complex metazoans (like us) lost a whole lot of tyrosine along the way, according to a recent Science paper. Why do we and our fellow animals have less of this amino acid than our unicellular nephews?

If you would be a single-celled organism, you would be absolutely free to divide and multiply according to your whims. Because they’re part of a multicellular organism, cells in your body don’t have that luxury: your body strictly regulates when cells divide. Damaged cells need to be told to die so that they can be replaced by other cells, for example.

Without this regulation, things go wrong. Cancer is an uncontrolled growth of cells: they cells  longer respond to the signals that tell them to stop dividing and start dying. Considering this, it is not surprising that metazoan cells have evolved intricate ways of detecting extra- and intracellular signals.

It's not easy being gre.. multicellular! Photo courtesy of lovelydead, Flickr.

One of these signaling mechanisms is the phosphorylation of tyrosine in proteins. Tyrosine is an amino acid that can be phosphorylated by proteins called tyrosine kinases. A signal from the outside of the cell activates the tyrosine kinase, after which the tyrosine kinase starts phosphorylating tyrosines in other proteins. The phosphorylation influences the activity of the proteins. In this way, the signal that came from the outside can be picked up and transmitted to the inside of the cell and is eventually translated into an appropriate response.

In their publication, Tan and colleagues show an inverse correlation between the tyrosine content of proteins and the complexity of organisms in metazoan lineages. The number of predicted tyrosine kinases in a genome is also inversely correlated with tyrosine content. In other words: the complexer an organism is or the more tyrosine kinases the organisms has, the less tyrosines there are for the tyrosine kinases to phosphorylate. In fact, the organism without any tyrosine kinases (Saccharomyces Cerevisiae, or baker’s yeast) has the most tyrosine of all metazoans!

Inverse correlation between metazoan complexity / # tyrosine kinases and tyrosine content.

This might seem strange at first sight, but Tan and his colleagues give an elegant explanation in their paper. At some point in time, the first tyrosine kinase evolved. Subsequent duplications allowed for the divergence of substrate specificity of the new tyrosine kinases. But by now, a lot of proteins that contained tyrosines, could become phosphorylated, that were never phosphorylated before. It is quit likely that some of these phosphorylations turned out to be disadvantageous.

Mutations that remove these ‘disadvantageous’ tyrosines, thus confer a fitness advantage for the organism. Positive selection on these tyrosine-removing mutations can explain the decrease in tyrosine residues in the metazoan lineage. By removing the non-beneficial tyrosines, the noise in the newly emerging signalling system was minimized and the specificity of the tyrosine kinases ensured. In the words of the authors:

… the implementation of tyrosine kinase signaling, as a biological innovation that probably assisted in the development of multicellular organisms, required system-level adaptive mutations.

So by reducing the total tyrosine content of the proteins, metazoans ensured that the tyrosine kinase signalling system reached its optimal effectiveness. The team made similar observations for other amino acids and their post-translational modifications, indicating that this principle is not unique for tyrosine phosphorylation.

So, that’s why we lost all that tyrosine!

Tan CS, Pasculescu A, Lim WA, Pawson T, Bader GD, & Linding R (2009). Positive selection of tyrosine loss in metazoan evolution. Science (New York, N.Y.), 325 (5948), 1686-8 PMID: 19589966

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