@article {Idrisdmd.119.089714, author = {Misgana Idris and Deanne J Mitchell and Richard Gordon and Neelima P Sidharthan and Neville J Butcher and Rodney F Minchin}, title = {Interaction of the brain-selective sulfotransferase SULT4A1 with other cytosolic sulfotransferases: effects on protein expression and function.}, elocation-id = {dmd.119.089714}, year = {2020}, doi = {10.1124/dmd.119.089714}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {SULT4A1 is a brain-selective sulfotransferase-like protein that has recently been shown to be essential for normal neuronal development in mice. In the present study, SULT4A1 was found to co-localize with SULT1A1/3 in human brain neurons. Using immunoprecipitation, SULT4A1 was shown to interact with both SULT1A1 and 1A3 when expressed in human cells. Mutation of the conserved dimerization motif located in the C-terminus of the sulfotransferases prevented this interaction. Both ectopically expressed and endogenous SULT4A1 decreased SULT1A1/3 protein levels in neuronal cells, which was also prevented by mutation of the dimerization motif. During differentiation of neuronal SH-SY5Y cells, there was a loss in SULT1A1/3 protein but an increase in SULT4A1 protein. This resulted in an increase in the toxicity of dopamine, a substrate for SULT1A3. Inhibition of SULT4A1 using siRNA abrogated the loss in SULT1A1/3 and reversed dopamine toxicity. These results show a reciprocal relationship between SULT4A1 and the other sulfotransferases suggesting that it may act as a chaperone to control the expression of SULT1A1/3 in neuronal cells.SIGNIFICANCE STATEMENT The catalytically inactive sulfotransferase SULT4A1 may regulate the function of other SULTs by interacting with them via a conserved dimerization motif. In neuron-like cells, SULT4A1 is able to modulate dopamine toxicity by interacting with SULT1A3, potentially decreasing the metabolism of dopamine.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2020/03/09/dmd.119.089714}, eprint = {https://dmd.aspetjournals.org/content/early/2020/03/09/dmd.119.089714.full.pdf}, journal = {Drug Metabolism and Disposition} }