What is it about the prion structure that makes it resistant to digestion by stomach acids?
It is known that Prp-C can be converted to a pathogenic scrapie (Sc) isoform through a conformational change in which the protein loses some of its alpha-helical content and becomes more beta-rich. However, the detailed structure of Prp-Sc is still unknown. It has only been possible so far to investigate this isoform using the low-structural-resolution techniques such as Fourier transform infrared spectroscopy and circular dichroism spectroscopy. The results suggest that the secondary structure of Prp-Sc is dominated by beta-sheets. Prp-Sc contains 20 percent alpha-helix and 50 percent beta-sheet, while Prp-C contains 40 percent alpha-helix and only about 5 percent beta-sheet. Prp-Sc is also insoluble in aqueous buffers as compared to PrP-C.
It is true that proteins are usually digested in the stomach, but the stomach acids only help in liquefying the ingested food and partially unfolding the proteins. The actual protein degradation is done by various proteases that are present in gastric juices. Our body uses a cocktail of proteases to shred the proteins in the intestine because different proteases have different specificities towards the various amino acid sequences. A common enzyme that is used in protease digestion studies is protease K. This protease has a broad specificity, which is why it is used commonly to assess the general susceptibility of a protein in question to protease digestion. Experiments have shown that Prp-Sc is much more resistant to protease K digestion than Prp-C. Studies also suggest that Prp-C is a very stable protein with a melting temperature higher than 50 C (the melting temperature differs depending on the strain of Prp used). Additionally, relatively high concentrations of common protein denaturants that are used in protein folding experiments, urea (>4 M) and guanidine hydrochloride (>2 M), are required to unfold Prp-C. Aggregated Prp-Sc is proposed to be even more stable thermodynamically than monomeric Prp-C, which puts a lower limit on how stable the prion protein is against different kinds of denaturing conditions.
Since the structure of Prp-Sc is not known, it is difficult to say exactly what the structural reasons are for the resistance of Prp-Sc to proteases. Unusual secondary and tertiary structure can influence the susceptibility to protease digestion, so can the aggregation if it produces a protected multimeric structure. It is likely that the sites that the proteases tend to attack are efficiently buried in the hydrophobic core of Prp-Sc so that they are inaccessible for proteases. One has to keep in mind that resistance to protease digestion is a relative parameter: given sufficient protease concentration and reaction time, Prp-Sc would be digested at least to some extent. However, it appears that the relevant time frame determined by the digestion cycle is insufficient to cut up the pathogenic Prp to render it benign.
Furthermore, even if Prp escapes the digestion by gastric juices, it still has to make it into the blood from the intestine. The intestinal wall usually prevents the entry of ingested proteins into the blood. It is true that prions manage to escape both defense mechanisms: they are not digested efficiently by the proteases and also manage to penetrate through the intestinal wall into the blood stream and ultimately into the brain. There is evidence that to cross the epithelial intestinal barrier prions can use tricks like recruiting a partner-protein (for example a protein called ferritin) for co-transportation across the intestinal wall or they can employ myeloid dendritic cells to assist in transport. The exact mechanism of this shuttling remains unknown and it is a topic of current research.
1. Saunders, S. E., Bartelt-Hunt, S. L. & Bartz, J. C. (2012). Resistance of Soil-Bound Prions to Rumen Digestion. PLoS One. 7(8):e44051.
2. Colby, D. W., Wain, R., Baskakov, I. V., Legname, G., Palmer, C. G., Nguyen, H. O. B., Lemus, A., Cohen, F. E., DeArmond, S. J. & Prusiner, S. B. (2010). Protease-Sensitive Synthetic Prions. PLoS Pathogens. 2010 6(1):e1000736.
3. Mishra, R. S., Basu, S., Gu, Y. P., Luo, X., Zou, W. Q., Mishra, R., Li, R. L., Chen, S. G., Gambetti, P., Fujioka, H. & Singh, N. (2004). Protease-resistant human prion protein and ferritin are cotransported across Caco-2 epithelial cells: Implications for species barrier in prion uptake from the intestine. Journal of Neuroscience. 24, 11280-11290.
4. Mckinley, M. P., Bolton, D. C. & Prusiner, S. B. (1983). A Protease-Resistant Protein Is a Structural Component of the Scrapie Prion. Cell. 35, 57-62.
5. Prusiner, S. B. (1998). Prions. Proceedings of the National Academy of Sciences of the United States of America. 95, 13363-13383.