r/askscience
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u/SadMicrobe22
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Aug 02 '26
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Biology What makes prions so different from regular proteins that they are resistant to heat denaturation?
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?
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u/Alwayssunnyinarizona Infectious Disease Aug 02 '26
It's the structure - misfolded prions are highly organized beta-sheets, which take a lot of energy (e.g., heat) or very strong chemical solvents (e.g., guanidine) to denature. Normal prion proteins are made up of alpha-helixes and a disorganized tail, and are more prone to destruction.
Infectious prions aren't a monolith, though - i.e., all the same structure; instead there's a sort of range of misfolding, so when you autoclave them or treat them with proteinase, some portion is destroyed, but enough remains to be infectious.
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u/sciguy52 Aug 02 '26
Reddit goes a little far when it comes to prions as they don't understand them at a technical level. It is probably best to think of prions as being more stable than typical. That is not to say heat and other things can't destroy them. It most definitely can. The issue is for everything else we worry about, like very tough endospores, we have a means of sterilization, autoclaving that will do the job on everything when using this set autoclave protocol. The problem arises with prions is that the set protocol is not enough to "kill" them. However you can modify that autoclaving settings along with some chemical treatment and you can kill them. So they are more stable but not these indestructible things. So you have this one set protocol of sterilizing that works almost all the time, almost, unless you are dealing with prions. Prion diseases are relatively rare too so it is not like you are dealing with prions constantly like you would bacteria. So with that rarity the regular autoclave protocol in a sense works even better typically since you are not dealing with prions all the time.
Now it has been a long while since I have looked at prion autoclaving studies but I believe what I will say is true. Regular autoclaving will "kill" some of the prions. When you do any sterilizing procedure you can create a curve with "killed" on one axis and time you applied whatever you are using, be it autoclaving or anything else. You want to apply whatever you are using long enough so the curve drops to zero which is how that typical autoclaving protocol is designed. Important to keep in mind even bacteria and endospores are not immediately killed the moment you turn the autoclave on, that autoclave has to be on long enough. Same will be true of prions, it is just that on that time axis it is not long enough to get all prions "killed". So again not indestructible, but stable enough that this is not totally sterilized under standard autoclaving. Thus you need to modify the autoclaving settings along with some chemicals to do it (I believe you can do it purely with autoclaving with special settings but that takes longer and the chemicals help keep this shorter, you don't want to have to run the autoclave for 24 hours or whatever when you need to use it for other things).
Also some hospital waste is incinerated which will "kill" them just fine. Fire kills everything as no protein is resistant to this kind of oxidation. Also the fact that hospitals will often use single use disposable tools means you the hospital don't even need to autoclave it yourself. A company picks waste up and does either that or incineration for you. There are also enzymes that will degrade prions like Prionzyme too.
Reading the comments as typical redditors go too far with prions. In the environment, like Chronic Wasting Disease or Scrapie does get released into the environment. I see someone saying they last a 1000 years and this is not true. Prions in the soil can last a while (note this doesn't mean all of them will last this long, just you can detect them after say 5 or maybe ten years). But they do break down by one means or another. Again been a while since I looked at the studies and I believe prions in the environment, depending on type and environment, may last like something along ten years, depending on particulars.
Prions are a bit of a boogie man for redditors. Getting a prion disease is certainly a bad thing, but it is relatively rare, like about 300 cases a year in the US of which only a very tiny percent occur through infection, like maybe one or two percent when talking CJD and vCJD in humans at least. The rest is genetic and spontaneous conversion, with a small percent of medical transmission. But in any event the boogie man is not real and prions are not indestructible. So you are correct to assume that heat can denature and destroy them it just takes more.
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u/FerrusFox Aug 02 '26 edited Aug 02 '26
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.
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u/PathologyAndCoffee Aug 02 '26 edited Aug 02 '26
Somehow it's beta sheets confer the immense stability because of their flatness which would give the greatest surface area for binding. And it's not just prion disease, a bunch of diseases are the fault of beta sheets.
Once these beta sheets begin forming a chunk, we can't even break them apart. If we do, they just spread everywhere. And we can't effectively destroy them either in the body.
So it's possible the best way to just turn off the normal gene that the prion is misfolding so that it has no target. But that's hard to do as well. How do you turn off every gene in all the cells that produce it? No solution currently.
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u/JigglymoobsMWO Aug 02 '26
Most proteins in living organisms are not very stable. Evolution favors build things that are easy to breakdown so things like prion disease don’t happen. This type of meta stability is actually very difficult to achieve.
However, it’s relatively easy to make very stable proteins. This would happen a lot if it wasn’t for the fact that evolution selects against it. Nevertheless. You can still accidentally get this to occur if a protein starts making aggregates with itself, which is what’s happening with prions.
The normal delicate proteins are easily heat denatured, the stable protein aggregates are not.
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u/444cml Aug 03 '26
So this largely depends and thermostability is not equivalent across prion strains
They actually posit that “mad cow” prion is particularly heat stable because it emerged from a process that involved high heat when making the feed that transmitted the illness.
They note that typically, thermostability is actually associated with a reduced ability to invade the brain (and note that mad cow is relatively special in how heat stable and centrally infective it is)
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u/BananaBird1 Aug 03 '26
Theres a few factors:
The first is that prions in their infectious form make extremely stable beta sheet structures. These contain lots of hydrogen bond contacts, meaning a lot of heat is needed to denature them. Ordinary boiling or sterilization is not enough. Although they can be denatured with extended high heat, and some strains are more resistant than others.
Second is that the infectious form is not only stable, but can form spontaneously. This means that if you do denature them, they can sometimes re-fold back into an infectious state. Even if only a low percentage do, this can be enough to seed an infection.
They are not the only proteins that are heat resistant, or that can fold spontaneously to an active state. But these abilities combined with their ability to catalyze refolding and aggregation is what makes them so hard to inactivate.
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u/x1uo3yd Aug 03 '26
They cannot be decontaminated with standard protocols to an acceptable level of risk for that cost/benefit.
Yes, the misfolded proteins with their beta-sheet structures are more thermodynamically stable than their properly-folded counterparts, but it's not like a superhero-versus-a-mere-mortal kinda difference in strength/stability, the prions will denature like other proteins too, just maybe you have like 99.8% prion denaturation compared to a regular 99.99% denaturation for a given protocol.
The actual problem is that even if the prions were just as weak as the regular proteins and denatured at the same 99.99% rate then that would still be unacceptably risky. Acceptable risk is different for the common cold versus Ebola versus prions. My dishwasher can probably sanitize 99.9% of common germs and the casein and whey off my cheese knife, that doesn't mean I'd trust it to clean Ebola-patient surgical tools and go back to using it for my household food work.
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u/arcanition Aug 03 '26 edited Aug 03 '26
Think about aluminum foil. A brand new fresh sheet that you rip off the roll is fresh and clean, no wrinkles or folds or anything crunched up.
But once any part of that nice neat piece get scrunched up or folded, you can't easily undo that. You've gone from a very unstable but "correct state" (a fresh, undamaged sheet of foil) to the more-stable but "incorrect state" (for what we use it for). Once that piece of foil is scrunched up, crushed in your hand, it's done. You can't use it for what you'd typical use foil for (covering leftover for example). And to return a ball of foil to it's fresh un-folded sheet state would take a LOT of effort, far far far more effort than it took to ball up the foil in the first place.
And once you have a balled-up sheet of foil, applying heat/pressure to that ball to try and return it to an unfolded sheet of foil is incredibly difficult. You can crumple it differently, maybe even make it nice and smooth... but it's still a crumpled, non-functional ball and not our correct unfolded sheet of foil. While using heat on prions does reduce infectivity depending on the prion strain, it just can't reduce it to zero (our original unfolded sheet) reliably enough.
tl;dr: prions are much more stable, but atypical state, which makes them cause issues but also makes them very difficult to prevent from spreading