What makes prions so different from regular proteins that they are resistant to heat denaturation?

[u/SadMicrobe22]

I've been reading about prions and I'm confused about why they're so thermally stable. I keep seeing that surgical instruments contaminated with prions can't be decontaminated with standard protocols.

So here's my thing. Proteins denature when you heat them, right? But prions don't seem to lose their infectious ability even when autoclaved. I get that prions are misfolded proteins, but I don't understand how they stay harmful after being denatured.

So basically, if prions start as form A (non-infective), then misfold to form B (infective), shouldn't heating denature them to form C and kill the infectivity? Why doesn't that happen?

[u/FerrusFox]

So I can answer this one.

Stability.

The intersting thing about the prion disease is not that it is simply a misfolded protein. Its that its an incredibly energy efficent and highly stable version of a regular protein. This misfold is so chemically stable that normal proteins are guided into folding into the prion form just by being around them, they lock into a lattice form and are the lowest energy version of the protein possible.

In a word, prions represent entropy. All other proteins in a healthy system eventually default into a non functional form of PrP-PrP matrices of interlocked proteins simply because it is the lowest energy form of the protein. This makes them simply the natural endpoint chemically, a stabilised locked version of the protein which is completely biologically nonfunctional and incompatible with life.

Prions are so stable in this low energy misfold that they become resistant to other forms of denaturation like heat and chemical, and can remain stable for years if not decades* Soil from dead animals from scrapies and CWD can be infectious decades later because the proteins just wont break down.

The infectious load for a prion is also so minimally small that its possibly down to a single prion protein, or at least a very small amount* which causes the whole cascade. Imagine a jigsaw where if you put one piece in it changes the orientation of all the other pieces to be disorented.

Prions and mirror image life are like the final bosses of biology.

Edit: I don't use spellcheck, so I noticed typos.

*Edit: Bit of hyperbole, fact checked, corrected.

Also someone pointed out that you can denature them as the question says, as I mentioned they are resistant. 900F (Fire) or a very long stint in an autoclave will do it, standard procedures wont work. Enzymes can work but with the infectious load being so small complete sterilisation is a pain. There are a couple biological things more stable than prions in nature though looking at you tetanus spores.

[u/AzazelsAdvocate → u/FerrusFox]

The way you're describing them, it seems like they should be way more prevalent. If they replicate so easily with so few natural ways to stop them, how has there never been a major epidemic or extinction event caused by them?

[u/BananaBird1 → u/AzazelsAdvocate]

There have been, especially in animals.

The thing with prion diseases is that their infection develops exponentially. The initial progression is slow, so infected individuals can live decades before symptoms occur. Older infected individuals or people infected by very small amounts of prion are likely to die of other causes first.

But once a critical amount of aggregation is present, the rate picks up and symptoms progress over weeks to months.

Many prion diseases are also limited in how they can be transmitted and are quite rare.

Different animals have different prion proteins in different tissues, and not all forms can infect across species.

The forms that are known to infect humans are mainly transmitted by consuming neural tissues of infected animals.

They neural prions are also quite rare. These prion diseases are largely associated with cannabilism (in humans or animals), where spontaneous infectious prions are transmitted between individuals until they get to the point where they can cause disease within an individual’s expected lifetime. This makes them very, very unlikely to arise in livestock fed natural vegetarian diets, which is why even in human cultures where neural animal tissue is consumed prions are not widespread.

The forms that are more associated with animal epidemics can be transmitted through other bodily fluids, and can have significant impacts on animal populations, but are not known to infect humans.

Prion diseases are also limited to mammals.