Aminoacyl-tRNA synthetases play a fundamental role in protein translation, linking transfer RNAs to their cognate amino acids. But in the hundreds of millions of years that they’ve existed, these synthetases (AARSs) have picked up several side jobs. One of these is to manage the development of vertebrate vasculature.
Multiple AARSs play roles in the development of the vertebrate circulatory system. During development, the serine enzyme SerRS downregulates the expression of vascular endothelial growth factor A (VEGF-A), preventing over-vascularization.
In addition, a combo synthetase for glutamic acid and proline, GluProRS, links up with other proteins to form the interferon-γ activated inhibitor of translation (GAIT) complex to block VEGF-A translation.
A piece of the tryptophan synthetase TrpRS also contributes to dampening angiogenesis by binding and blocking VE-cadherin receptors on endothelial cells so they can’t link together to form blood vessel lining.
Meanwhile, a fragment of the tyrosine synthetase TyrRS appears to promote the growth of blood vessels by stimulating migration of those endothelial cells.
When these functions arose in evolution
According to Scripps Research Institute biochemist Paul Schimmel, the addition of accessory domains that perform such tasks parallels major events in the evolution of circulation. The first blood vascular system, which lacked the endothelium present in modern vertebrates, probably arose in a common ancestor of vertebrates and arthropods around 700 million to 600 million years ago. Around this same time, TyrRS acquired a glutamic acid–lysine–arginine motif that today is thought to promote angiogenesis. Then, around 540 million to 510 million years ago, an ancestral vertebrate evolved a closed vascular system, with blood pumping through vessels lined by endothelium. At some point around that same time period half a billion years ago, the TrpRS picked up a WHEP domain, which today regulates its ability to block angiogenesis. In addition, SerRS acquired a domain unique to this enzyme, which now prevents over-vascularization in developing zebrafish, and likely other vertebrates.
GluProRS’s role in angiogenesis, on the other hand, doesn’t seem to be so precisely timed to the evolution of vasculature. A linker protein tied together the AARSs for glutamic acid and proline enzymes around 800 million years ago, before circulatory systems existed.
- A primitive circulatory system appears in the common ancestor of arthropods and vertebrates. Endothelium-lined blood vessels are not yet present.
- TyrRS acquires a domain that today promotes angiogenesis.
- The closed circulatory system, with blood vessels lined by endothelial cells, appears in an ancestral vertebrate.
- TrpRS acquires a domain that blocks angiogenesis in modern animals.
- SerRS acquires a domain that today regulates vascular development in zebrafish and likely other vertebrates.
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