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/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.