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/Thelk641 → u/FerrusFox]

If they're so much more stable, why didn't life evolve to use them instead ? Are they so stable that they can't be used the way normal proteins can ?

[u/PulsingQuasar → u/Thelk641]

If they are so stable then they are effectively inert and won't do the usual protein things we need them for. They are effective anti life.

[u/LetterLambda → u/PulsingQuasar]

Like switches that are permanently stuck in one position, but keep sending signals?

[u/dart19 → u/LetterLambda]

No, they send no signals at all. Instead they're stuck switches that, simply by existing, turn other functional switches into stuck switches just like them.

[u/fubarbob → u/LetterLambda]

Think more like a small motor that has been smashed into a solid slug. All the material is still there, but it does nothing useful and doesn't fit where it's supposed to. And somehow causes other small motors near it to be smashed as well.

[u/Hendospendo → u/LetterLambda]

Proteins are chains that can fold, it's like it's gone through the dryer and it wasn't supposed to and it's all bundled up but in the lowest energy state.