Re: why are prions resistant to proteases?

Dear questioner,

Prion research can be pretty confusing. I had a look at the prion research literature to prepare this answer and found many articles on protease resistance of the prion protein. To answer your question, we need to think about the structure of prion proteins.

One of the most interesting early discoveries about prions was that there is a "normal form" of prion, called PrP^C, found in the membranes of brain cells. No one is really sure what it does - in fact, you can knockout the gene that makes it in mice and it doesn't seem to make much difference to them. Prion proteins are even found in yeast (which don't have brains) so whatever they do, it's important to all kinds of organisms.

PrP^C is a fairly small protein and so it was quite easy to determine its structure. We find the structure of molecules using a tool called X-ray crystallography, which is quite complex, but basically it's like taking a picture of a molecule. There is a large database on the internet called the Protein Data Bank, containing the structures of many proteins - you can go there and have a look at human prion protein. Now, those coloured corkscrew shapes are called helices and they define the normal form of a prion protein.

When brains become diseased with prion diseases, we see an accumulation of abnormal prion protein, called PrP^Sc. We believe that this has quite a different structure to the normal protein - but we don't know yet exactly what it looks like, though we do know that it loses the helices found in the normal prion protein. So biochemists have devised a number of tests which can be used to describe the protein and one of these is protease resistance.

Proteases are enzymes that cut other proteins into pieces. They can start at the ends of a protein and "nibble" it, or in the middle. They usually work by recognising a particular part of their target protein - you probably know that proteins are made of smaller units called amino acids and a protease will recognise short sequences of these units. However, to digest the protein, these recognition sites have to be accessible to the protease - not buried away inside the protein structure.

It was discovered that a particular protease, called Proteinase K, can be used to distinguish different forms of prion protein in different prion diseases. So when we talk about prions and protease resistance, we are really talking about their resistance to digestion using Proteinase K. What's more, the term "protease resistant" is a little bit misleading. All prion proteins are digested by Proteinase K - what differs is the rate at which they are degraded and the specific fragments of protein that are produced. To answer your original question - some forms of prion protein are protease-resistant (to Proteinase K) because their shape makes it difficult for the protease to cut them - maybe because the recognition site on the protein is not accessible. So what we are doing is using Proteinase K to tell us something about the shape of the protein, because we don't know its exact shape (structure).

I hope this helps with your question. A good website for prions and prion diseases is MadCow.org - it has not been updated in a long time, but there is still a lot of information there. The Wikipedia prion page (http://en.wikipedia.org/wiki/Prion) is also good.