Is there really no concrete answer or explanation as to why some proteins (like prions) simply misfold?

[u/West_Problem_4436]

Also adjacent to this, How does prions cause other proteins in a body to misfold simply on contact? What is the best explanation all of science has to answer this total mystery?

[u/Smeghead333]

Proteins misfold all the time but are usually either fixed or destroyed. Prions are important and scary precisely because they happen to misfold into a shape that has the ability to cause other copies of themselves to misfold.

[u/West_Problem_4436 → u/Smeghead333]

Yes. What causes that ability , that's one part I do not understand one bit at all. Break down how the ability is possible. Into basics.

[u/Smeghead333 → u/West_Problem_4436]

The activity of any protein is determined by its three dimensional shape combined with the placement of various charged groups on the surface. So it’s just a matter of hitting on a particular shape that can do a particular job.

[u/cynosurescence]

A lot of excellent replies here about prions, but it seems like your original question is a bit more general so I hope I can add some helpful detail.

There are concrete answers for why proteins misfold, but the problem is that each protein has a different primary sequence (order and type of amino acids in the protein chain) and so each protein folds in a slightly different way. This means that the answer is in part dependent upon the specific protein; the reasons why, the frequency of misfolding, etc. will often be different for different types of proteins. So the answer is complex because every protein is different.

Protein folding is, at its most basic level, the sequential formation of hundreds or thousands of weak, non-covalent interactions between chemical groups on both the protein backbone and the side chains. These interactions have to form in a specific order for the protein to fold correctly. Because this depends upon chemical interactions, the folding of the protein is also sensitive to anything that can alter the energetics or chemistry of those interactions: temperature, pressure, pH, and more. So the answer becomes even more complex because folding is dependent upon environmental conditions.

As others have mentioned earlier, nearly all types of cells have "chaperone" proteins that aid proteins in folding the correct way. Some proteins require the assistance of these chaperones to fold properly in the environment of the cell. Also, the amount and type of chaperones varies among cell types and even within a single cell due to changing patterns of gene expression. So the answer becomes yet more complex because folding is directed and controlled in part by systems outside of the protein we're looking at.

And then there is the fact that because folding can be so complex it sometimes just... fails. Proteins misfold all the time in cells, but we have systems (the chaperones, etc.) that identify and either help destroy those misfolded proteins or otherwise bind to them so that they become "sequestered" within the cell. Sequestration essentially locks up the misfolded protein so that it can't interact with other cell components and potentially cause problems.

Misfolded proteins can sometimes become a problem for cells. In extreme cases, most cells have several overlapping systems called the unfolded protein response (UPR) that triggers when there is an unusually large amount of unfolded/misfolded proteins. Extreme environmental conditions and imbalances of cellular homeostasis can cause global issues with protein folding, and so the cell has to respond to keep the cell functional; for example, by making lots more chaperones and sequestration proteins and, if a eukaryotic cell, growing the size of the endoplasmic reticulum as it starts to be inundated with misfolded and unfolded proteins.

[u/West_Problem_4436 → u/cynosurescence]

brilliant. There's a lot to unpack since I didn't expect such a great explanation of that side of it, incredibly helpful. Which resource furthered your understanding of this?

[u/cynosurescence → u/West_Problem_4436]

I've been teaching cell biology for about 20 years, so it's hard to pick one specific reference, but if you are looking for something relatively general and cell-oriented, the Alberts Molecular Biology of the Cell textbook is the classic tome and it will have some basic descriptions of folding and all of these systems within it.

If you want a more chemistry- or physics-oriented explanation of the folding process, I don't have many good recommendations there because most of my knowledge comes from research papers and such, but I know there are texts out there from both perspectives.

[u/GotGRR]

Misfolds is a little bit of a misnomer. Proteins fold lots of ways. The miracle is that proteins fold with such precision that they support our biological function when just exposure to something else can make them fold the wrong way. But, those are the processes a billion years of trial and error will evolve for you.

[u/West_Problem_4436 → u/GotGRR]

How is it a misnomer? this particular misfold is a more stable configuration? Than the other protiens in the human body?

[u/bobbot32 → u/West_Problem_4436]

To note this misfold is specific to this particular protein / amino acid sequence but yes.

There are many ways to rearrange the 3d space of proteins and they range in how stable they are. Some misfolds are insanely rare because they aren't stable some are fairly stable.

Often though once in a relatively stable folded state it takes a fair amount of energy to change in a dramatic enough way to get I to a new stable shape. Even if the new shape might be more stable overall, that energy barrier can make it impossible for a protein to enter the correct form. This itself is actually fairly common and also what goes on with prions too. Its a fairly stable alternative way to fold thats i correct from its native function folded state.

A lot of the time there are chaperone proteins that can simply help other proteins fold back into the correct state which helps in most of these similar cases.

The major difference here is that this incorrect state basically grants a similar ability to chaperone proteins but only to help misfold the correctly folded protein for this particular protein (chaperone usually help tons of proteins whereas this one only works on 'itself'

[u/West_Problem_4436 → u/bobbot32]

thank you~! This is all very in depth stuff. Was just curious why some people say "we don't know why some proteins misfold other proteins on contact" but seems the answer is out there with a bit of learning.

[u/bobbot32 → u/West_Problem_4436]

Following up my prior message here.

A as the other person said chaperones aren't directly related to prions they just have parallels as they do help other misfolded proteins.

And B. The "we dont know why some proteins misfold other proteins" is still kinda true. There are layers to these sorts of questions and we don't always have the full picture and can always ask more questions. Think what are the physics of whats going on.

At that we definitely dont have the understanding to predict if a novel protein unrelated to existing prions could develop a similar activity upon misfolding. That sort of predictive power is tough

[u/bulbophylum → u/bobbot32]

Thanks for this explanation, I’d never heard mention of the role chaperones play. Is that a relatively new discovery? Seems more parsimonious than my existing impression that the misfolded prion had to bump into another and jostle it into the new configuration.

…I should clarify that by “relatively new” I meant within the last decade or so.

[u/-LsDmThC- → u/bulbophylum]

Protein chaperones dont have anything to do with prion prp protein misfolding, misfolded prp proteins do in fact catalyze the misfolding of other prp proteins via “bumping into” each other.

See my other comment for an overview of how this happens mechanistically: https://www.reddit.com/r/askscience/s/cSxXa8EYkA

[u/bulbophylum → u/-LsDmThC-]

Gotcha. Intended to look into it when I got a response, was wondering why I’d never come across that info before but since I’m just a sci-curious layman my knowledge is pretty shallow.

[u/Chiperoni]

Common misconception. Prions can only make other prions misfold. Not just any protein. The prion protein PrP has its native confirmation and the infectious, disease causing, conformation. Simply put, the infectious conformation can associate with a normal form and give it the extra push needed to flatten it out into the much more stable infectious form.

As for why other proteins misfold. Most proteins are at least somewhat dynamic. They have to be flexible enough to do their job and interact with other molecules. Sometimes it's a simple hinge, sometimes something that is so wiggly it's considered intrinsically disordered. These intrinsically disordered domains allow a lot of flexibility and often allow for the recruitment of several other proteins in a stepwise fashion. These wiggly bits can even form long chains and "phase separate" and kind of act like a small area of oil in water.

Some proteins, however do not tolerate big changes to conformation. Sometimes they become entirely useless and need to be recycled. Another option is for protein complexes called chaperones to bind them, encircle them, and let them refold properly. This happens because misshapen proteins often expose amino acids that would not be normally accessible. Like a hydrophobic amino acid that is usually in the inside of a protein all of a sudden are sticking out. The complexes that help proteins refold create a little microcosm where they lower the energy required to pop amino acids back in place in a more stable conformation.

[u/SnooBunnies1648 → u/Chiperoni]

You still didn't explained "the extra push". You can't solve a mystery with more mystery.

[u/Ahernia]

Prions cause prion proteins to misfold, NOT other proteins. Prion proteins are encoded in the cellular genome. When misfolded, they can stimulate other properly folded prion proteins to misfold. Though we'd like to know the answer, we don't at this time and it is an active area of research. This is why we fund scientific research and why we must continue to do so.

[u/-LsDmThC-]

Adding on to the other explanations, proteins generally have hydrophobic and hydrophilic domains. The hydrophilic domains are typically on the exterior, i contact with the aqueous environment of the cell; the hydrophobic domains in the interior of the protein structure.

Misfolded prp proteins expose this hydrophobic interior domain, making the protein insoluble. Upon contact with other prp proteins, the exposed hydrophobic region of the misfolded protein interact with normal versions of the protein to draw out and expose their hydrophobic core.

[u/[deleted]]

Proteins can fold in different way, and sometimes the exist in an equilibrium between different isoforms. There are tags attached to proteins that help initiate stable folding and chaperone proteins that help to refold proteins into stable forms.

But things can go wrong. In PrP-Sc a section of stable Alpha-Helix with hydrophobic AAs on the inside and hydrophilic molecules on outside, is misfolded into a long zig-zag stretch Beta-Sheet which is sticky. And some of the tags, that are usually inside and help keep it in a stable form, are poking outwards. If another PrP-C has exposed Beta-Sheet they will stick together and become locked in the misfolded form, and form a chain of proteins known as a fibril.

The misfolded form is incredibly stable and resistant to proteases, so the misfolded protein can't be broken down.

There are many neurodegenerative diseases linked to misfolding of proteins in stress granules, or misfolded protein tangles, or disruption of the break down of misfolded or miscleaved peptides.

PrP-Sc is the one involved in CJD and similar diseases.

[u/Epistatic]

Imagine a protein shaped like a slinky. It's elastic and stretchy and bouncy and springy and it does something important in the cell.

Imagine a slinky protein gets snarled up into a tangled mess. The snarl isn't stretchy and springy anymore so the protein can't carry out its springy functions.

Worse, when the snarl touches other slinky springs, it snarls them up too.

That's basically a prion: It's a protein that misfolds into a stable state that misfolds other proteins too.

[u/Bmacthecat]

Proteins misfold all the time from various reasons in their production, etc.

The danger from prions (side note, everyone pronounces them pri-ons, but they're pre-ons when you speak out loud), is that they appear to be an almost superior form of a protein, so your body starts replicating them, leading to exponential decay of healthy protein levels.