Despite the fact that mucus and bicarbonate are important macroscopic components of the gastric mucosal barrier, severe acidic and peptic conditions surely exist at the apical membrane of gastric glandular cells, and these membranes must have highly specialized adaptations to oppose external insults. Parietal cells abundantly express the heterodimeric, acid-pumping H-K-ATPase in their apical membranes. Its -subunit (HK), a glycoprotein with >70% of its mass and all its oligosaccharides on the extracellular side, may play a protective role. Here, we show that the extracellular domain of HK is highly resistant to trypsin in the native state (much more than that of the structurally related Na-K-ATPase -subunit) and requires denaturation to expose tryptic sites. Native HK also resists other proteases, such as chymotrypsin and V8 protease, which hydrolyze at hydrophobic and anionic amino acids, respectively. Removal of terminal -anomeric-linked galactose does not appreciably alter tryptic sensitivity of HK. However, full deglycosylation makes HK much more susceptible to all proteases tested, including pepsin at pH <2.0. We propose that 1) intrinsic folding of HK, 2) bonding forces between subunits, and 3) oligosaccharides on HK provide a luminal protein domain that resists gastric lytic conditions. Protein folding that protects susceptible charged amino acids and is maintained by disulfide bonding and hydrophilic oligosaccharides would provide a stable structure in the face of large pH changes. The H-K-ATPase is an obvious model, but other gastric luminally exposed proteins are likely to possess analogous protective specializations.