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Characterization of human mutations in phosphorylatable amino acids of the cytosolic regulatory tail of SLC9A1.

Research paper by Claudia C Alves, Yike Y Ma, Xiuju X Li, Larry L Fliegel

Indexed on: 28 Aug '14Published on: 28 Aug '14Published in: Biochemistry and cell biology = Biochimie et biologie cellulaire



Abstract

The NHE1 isoform of the mammalian Na(+)/H(+) exchanger is a ubiquitous plasma membrane protein that regulates intracellular pH in cells by removing one intracellular proton in exchange for one extracellular sodium. Genetic defects in NHE1 have been shown to affect the growth and motor ability of mice, but mutations in humans have not been studied. NHE1 has a cytosolic C-terminal regulatory domain of approximately 300 amino acids. We investigated the functional effects of two human mutations found in the regulatory phosphorylatable amino acids Ser(703) and Ser(771). A Ser703Pro mutant protein had essentially the same activity, expression, and targeting as the wild type NHE1 protein. In contrast, the Ser771Pro protein had reduced activity and expression of NHE1 protein, though cell surface targeting was normal. In dual pulse assays the Ser771Pro mutant was not further activated by sustained intracellular acidosis but displayed an unusual activation by brief pulses of acidosis. The results demonstrate that the Ser771Pro human genetic mutation has significant and detrimental physiological effects on the activity of the NHE1 protein, SLC9A1.