transcription mRNA coding for interleukin 2
NFAT has a sorting signal that would normally direct it to the nucleus, but in unstimulated cells this is masked by a phosphate group, so NFAT remains in the cytoplasm and interleukin 2 is not made. However, when foreign proteins, for example, any beginning with f-met (page 171), activate the T lymphocyte, they cause the concentration of calcium ions in the cytosol to increase (an increase of calcium concentration is a common feature of cell stimulation to be described in Chapter 16). Calcium activates a phosphatase called calcineurin, which removes the phosphate group from many substrates including NFAT. NFAT then moves to the nucleus and activates interleukin 2 transcription. The released interleukin 2 activates other immune system cells that attack the foreign body. Cyclosporin blocks this process by inhibiting calcineurin, so that even though calcium rises in the cytoplasm of the T lymphocyte, NFAT remains phosphorylated and does not move to the nucleus.
Medical How Protein Mistargeting Can Give You Kidney Stones Relevance Primary hyperoxaluria type 1 is a rare genetic disease in which calcium oxalate 10.3 "stones" accumulate in the kidney. Healthy people convert dietary glyoxylate (from plants, see page 297) to the useful amino acid glycine by the enzyme alanine glyoxylate aminotransferase (AGT) (page 250). AGT is located in peroxisomes in liver cells. If glyoxylate cannot be converted to glycine, it is instead oxidized to oxalate and excreted by the kidney, where it tends to precipitate as hard lumps of calcium oxalate. Two thirds of patients with primary hyperoxaluria type 1 have a mutant form of AGT that simply fails to work. However, the other third have an AGT with a single amino acid change (G170R) that works reasonably well, at least in the test tube. However, this amino acid change is enough to make the mitochondrial import system believe that AGT is a mitochondrial protein and import it inappropriately, so that no AGT is available to be transported to the peroxisomes. For the clinician, the mistargeting of AGT in primary hyperox-aluria type 1 poses an unusual problem, namely, how to explain to a patient that the way to cure their kidney stones is to have a liver transplant!
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