Protein Modification Determines Enzyme's Fate

Biochemistry and Molecular Biology 1 Proteins PRPS1 and PRPS2 are involved in the production of new nucleotides, the building blocks of DNA. The researchers had previously learned that PRPS2 is arginylated while PRPS1 is not. The team also knew from prior work that PRPS2 plays a role in cancerous growth, as cancer cells reproduce rapidly and need a constant source of nucleotides in order to keep up a fast rate of growth.
In the current study, the team got further clues that arginylation played a role in the different roles of PRPS1 and PRPS2 when they examined cells in which arginylation had been blocked by making the enzyme that adds arginine, ATE1, inoperative.
They found that these cells had problems with making purine nucleotides, the As and Gs of the DNA sequence. The genetically modified cells also made more serine and glycine amino acids than normal cells, a further sign that purine synthesis was impaired. Because both PRPS proteins are involved in purine nucleotide synthesis, they were clear candidates for being subject to regulation by arginylation.
When the team introduced arginylated forms of PRPS1 and PRPS2 into cells, they found that PRPS1 was unstable and quickly degraded, while PRPS2 survived arginylation.
The structure of PRPS1 mRNA is likely to slow down the process of translation, the researchers believe, perhaps making that protein vulnerable to degradation once it is arginylated. Because PRPS2 mRNA lacks the same obstructions to translation, it appears able to survive arginylation without being targeted for degradation.
Knowing that PRPS2, which has been implicated in driving cancer, is regulated by arginylation provides a potential “switch” for tuning that activity. And the importance of mRNA structure in how a protein is eventually treated could give another way of targeting PRPS2’s activity and turning it down to prevent the uncontrolled growth seen in malignancies.