pH uniquely modulates protein arginine methylation

Abstract

Wen Xie1, George Merz2 and Robert B. Denman3*

Protein arginine methyltransferases (PRMTs) function in the alkaline milieu of the nucleus and at neutral pH of the cytosol. Accordingly, several PRMTs are broadly active over a range of pHs. We investigated the effect altering pH had on protein arginine methylation using a variety of defined substrates, recombinant PRMTs and cell extracts.We demonstrate that pH-induced alterations in the extent of methylation and the methyl-product formed depend both on the particular substrate assayed and the PRMT that modifies it. We also find that transient intracellular alkalinization of mouse embryonic P19 neurons by NH4Cl results in sustained changes in substrate methylation. Altogether our results are consistent with a hypothesis in which altered substrate methylation resulting from pH-induced changes of PRMT activities coupled with low levels of demethylation may provide the long-term tag(s) necessary for the formation and maintenance of “molecular memory”.