Human gastric (H⁺ + K⁺)-ATPase gene: Similarity to (Na⁺ + K⁺)-ATPase genes in exon/intron organization but difference in control region

The human gastric (H⁺ + K⁺)-ATPase gene (15 kilobases) was cloned, and its nucleotide sequence was determined. The gene has 22 exons and codes a protein of 1,035 residues including the initiator methionine (M_r = 114,047). A conserved lysine-rich sequence with inserted glycine residues was found near the amino terminus of the enzyme. The phosphorylation site and pyridoxal 5′-phosphate- and fluorescein isothiocyanate-binding residues found in the rat and pig enzymes are also conserved in the human enzyme. The positions of introns in the human (H⁺ + K⁺)-ATPase gene are essentially the same as those in the human (Na⁺ + K⁺)-ATPase α and αIII subunits; but the first introns of the two enzymes are difficult to align, and unlike in the (Na⁺ + K⁺)-ATPase gene, the sixth exon in the (H⁺ + K⁺)-ATPase gene is not separated by an intron. Furthermore, the ninth intron is located two bases upstream of the position for the corresponding intron of the (Na⁺ + K⁺)-ATPase αIII subunit. The similarity in organization of these two ATPase genes and the homology in the primary structures of their proteins (∼60%) suggest that these two genes were derived from a common ancestral gene. However, the 5′-flanking regions of the genes for (H⁺ + K⁺)-ATPase and the (Na⁺ + K⁺)-ATPase α(+) subunit show no apparent sequence homology, indicating that their transcriptions are regulated differently. The control region of the fast-twitch sarcoplasmic reticulum Ca²⁺-ATPase gene also showed no sequence homology to that of (H⁺ + K⁺)-ATPase. The 5′-flanking region of the (H⁺ + K⁺)-ATPase gene contains potential binding sites for RNA polymerase II and various transcriptional regulation factors and several direct and inverted repeat sequences which may be important for specific and controlled expression of the gene in gastric parietal cells. There are two polyadenylation signals in the 3′-flanking region of the (H⁺ + K⁺)-ATPase gene, but the sequence of this region shows no homology to those of the corresponding regions of the genes for the (Na⁺ + K⁺)-ATPase α and αIII subunits.