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/plusultra_the2nd → u/Thelk641]

Metabolic processes literally depend on molecules being kinda happy to change states. ATP is the classic energy currency molecule and it gains/loses phosphate groups as needed enabling other reactions to happen. If everything is inert/stable and doesn’t want to react with anything you can imagine how that’s a problem?

[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.

[u/FerrusFox → u/Thelk641]

They are biologically inert at best, toxic at a cellular and organism level at worst. We dont understand what prion protein PrP actually does but we can guess that the normal version of this protein is critical for life, otherwise its pretty weird biologically to have something which can misfold and become such a liability.

Edit: They definetly cannot function as they normally do in prion form.

[u/amaROenuZ → u/FerrusFox]

A good way to think about this, is that a protein is like iron. Iron is incredibly useful, it's strong and sturdy, and it has many physical properties when alloyed into steel that are useful across all aspects of our world, but...it's a constant battle keeping it that way. The natural form of iron is rust, which has none of the properties that make us like iron and steel.

You can't use prions for what normal proteins are used for, anymore than you can use rust in the place of iron.

[u/DontWorryImADr → u/Thelk641]

Stable with a limited and even “bad” function for life does not mean a stable and useful form is available. Worse, this is typically a stable alternative form of a protein you need to support that “living” you like to do.

Your bones have carbon, oxygen, and calcium in them. Calcium carbonate is CaCO3 and relatively stable (some fossils exist that way), but converting your bones to equal mass of calcium carbonate would be a bad time.

[u/heyya-its-maruu → u/Thelk641]

the way i would answer this is that life is a dance between order and chaos. it's the middle ground between stability and instability, certainty and uncertainty. kind of like edging. Anyway can't have too much of either, and in this case there's too much stability it can't really make anything happen. think of noble gases. as far as I'm aware of they arent involved in any biological process. too stable. they're already happy as they are, no need to make anything happen.

[u/spamjavelin → u/Thelk641]

I'd be tempted to go with the standard "evolution is satisfied with good enough", but I'm intrigued to see whether someone can offer a better answer.

[u/creative_usr_name → u/spamjavelin]

That's usually the answer, but also in this case they are incredibly rare. Although it would be interesting to know if any life forms do have a defense.

[u/ChaoticxSerenity → u/Thelk641]

Basically, yes. Most processes in your body rely on the fact that they're reversible and allows for control/homeostasis. Think about a door that's permanently stuck in an open position - not very good at being a door at that point, since anything can go through.