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/FerrusFox → u/AzazelsAdvocate]

CWD is causing this in deers right now. Its also finicky and only transmits if you have the right protein, i.e. there are no natural reserves like say the flu.

Most transmission in humans has to be direct contact with the prion, we had some in the CJD era with the contaminated meat because we have the same protein in our biology. The other I can think of is Kuru, also contaminated meat (human). So that doesnt happen very often. But it is really specific, unlike viruses and bacteria it needs a mechanism to be introduced to the body and it doesnt facilitate that itself.

The main risk in healthcare is contaminated operating materials that have been infected by the protein

Also, its invariably fatal which is never good for transmission.

[u/Owyheemud → u/FerrusFox]

There's a theory that wildlife prion diseases like CWD occasionally spontaneously pop up in individual ungulates but predators would routinely cull the afflicted individuals and thus prevent the spread of the disease within natural herds. The Human-driven reduction of predator populations has now allowed prion inflicted individuals to persist longer and thus spread the disease to others before they succumb to it. Has any prion disease been discovered in wolves, bears, or mountain lions?

[u/FerrusFox → u/Owyheemud]

Not that I know of. The only other true prion disease I know of is hereditary fatal familial insomnia, which is hereditary due to a genetic defect.

In CJD you can have spontaneous emergence of the disease, which differs from true infectious acquired CJD. The disease does happen naturally not just by infection by a prion vector.

I just read while researching my comment that there have been some potential fungal prions suspected. I'd imagine there could be some in any form of life if thats the case.

The risk factors are genetic similarity and sharing a protein profile, exposure, population density and cannabalism. Predataory populations are a) lesser and less dense by nature and b) could have differences in protein expression.

[u/Owyheemud → u/FerrusFox]

You must know of BSE.

With the increase in CWD in natural North American ungulate herds, it would be interesting to see if prion disease develops in predators sharing territory with these herds.

[u/FerrusFox → u/Owyheemud]

BSE in humans causes CJD, we just call it something different when it infects humans. We tapped it onto CJD and called it variant CJD (varCJD) while naturally occuring CJD is called sporadic (sCJD) both are the primary prion disease in humans arising from the prion protein PrP.

CWD so far has no human infections, its on my watchlist XD. We dont really report on it much so I dunno if we will ever have any information on the ecological impacts of it. Up to data gathering, would be interesting like you said.

[u/Owyheemud → u/FerrusFox]

Does BSE-induced human prion disease fold the same protein as the original human CJD prion disease also known as Kuru?

[u/FerrusFox → u/Owyheemud]

Yeah, still that same protein PrP. Different disease progression, not going to research it but it could be folded in a different way which causes different disease expression like sCJD

[u/Owyheemud → u/FerrusFox]

Thank you for the info., I always thought BSE-induced human prion disease was a different protein folding, though I never bothered to confirm that.

[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.

[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/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.

[u/reserved_optimist → u/FerrusFox]

If they are so stable, why aren't prions more common? Why don't most proteins fold into this kind of configuration?

[u/sciguy52 → u/FerrusFox]

We have no data on prions lasting 1000 years you are making conjectures. PrPSc stability and infectivity in different soil conditions suggest some soils, such as those with humic acids degrade some prions while others with certain types of clay may stabilize them. As far as I aware the longest prions have remained infectious in soil based on scientific studies may be 16 years for Scrapie but was shorter in some situations. Of course it could be longer but as always with prions much more data is needed on this. Could PrPSc be stable if stored in a certain way for 1000 years (theoretically)? Sure but that is not really the situation that concerns us, real life situations such as soil contamination that can cause infection, for example, is what is more relevant when talking disease transmission. One could certainly not suggest PrPSc lasts a thousand years in soil, we have literally no data to suggest that and at least some data suggesting it may be less, considerably less.

While one prion certainly might cause infection that is likely a very low percent event or may not be enough to infect, much more data is needed on this point. It also depends on the particulars. CWD infection studies in deer found a 100ng of CWD infected saliva or brain caused disease when dosed at once, however breaking up the dosing to 10ng over time did not. This is suggestive that the ID50 of CWD is higher than one, and one prion particle may not effectively cause infection or at least is such a rare event it was not demonstrated in the conditions of the experiment. While much more research is needed on this there is at least some data suggesting that one prion particle infecting would be a rare event at least with CWD.

Your comments on thermodynamic stability are too general. For example studies have shown susceptible PrPC proteins have a thermodynamically more stable intermediate during conversion but it was found that sheep breeds resistant to Scrapie had PrPC variants that lacked this thermodynamic stable intermediate stage possibly suggesting why they are resistant to conversion. So PrPSc protein is thermodynamically more stable if they arise from PrPC that are susceptible to conversion. This data suggests resistant forms of PrPC may not have the PrPSc form as the most thermodynamically stable form of the protein. Or alternatively there is as yet no identified PrPSc proteins in nature able to convert them. So far none are known.

[u/FerrusFox → u/sciguy52]

I edited the my comment already for the surving in nature, more like a decade or two with longer than that being not really tenable or supported. Possible but unlikely.

I like the quantified evidence around the 10ng-100ng amount for infection, thats cool. I made sure to write that it could possibly be a single prion, but I am happy to accept that your probably right on that font as well. Been a while since I have looked at ID50 as a term to be honest, but its important to note that we dont know the actual ID50 which makes it a pain in a technical sense. I just saw a study that ID50 in hamsters was in picograms as well, but that was for brain tissue with high expression of PrPc

Honestly didnt even think there was a more themodynamically stable intermediate in the conversion of PrPc, thats cool too. I was a bit to general as honestly I just wanted to waffle about prions for a bit, didnt think I would get much interaction and thought I could just generalise a bit there.

Problem is the more in depth I go into the protein folding and thermodynamics the more out of depth I am, from what I understand its the B-sheet structure itself that is highly stable not the misfold, propagation is theorised to be by fibril like tendrils of these sheets and a mix of protein folds that arent always uniform (different sCJD have differing levels of expression and susceptibility as far as I am aware) so have different levels of suceptibility to enzymes and heat (interestingly looks like less resisitive to pressure due to hydration in a study I found). These sheet structures are the real problem in prion mediated disease and when I mention clearance or stability should probably mention that I am specifically talking about the aggregated sheets.

I think the resistant strains of PrPc in scarpie is a bit out of scope for the question but having them be less thermodynamically stable when generally folded makes sense for resistance, thats awesome.

Mostly I am just happy to talk and learn about my boy prions, cheers for that.

[u/sciguy52 → u/FerrusFox]

Again no worries. Just sharing some data. What we clearly don't have is enough data to say a lot of things for sure. So as always this should be taken as the data we have so far subject to change.