Read with caution!
This post was written during early stages of trying to understand a complex scientific problem, and we didn't get everything right. The original author no longer endorses the content of this post. It is being left online for historical reasons, but read at your own risk.
I’ve been trying to better understand the world of “protein helpers” – the other proteins that help client proteins achieve or retain their native state conformation. Seems like they could be pretty helpful in understanding protein conformation diseases, how misfolding gets out of control, and maybe even how/when to intervene, if we could figure out how they work.
There are a couple of different classes of these proteins. Heat shock proteins are transiently expressed “protector proteins,” activated by an ancient signaling pathway in response to stress. They’re misleadingly named because they are upregulated not only in response to heat, but also oxidative stress and a bunch of other stresses. Molecular chaperones are a subset of heat shock proteins – the most conserved among them. Their role is to help other proteins to achieve their native state, and prevent the formation of aggregates.
Here are some facts I learned recently about heat shock proteins:
- They are non-specific and “promiscuous” – they interact with lots of clients and don’t contain any structural information about how these client proteins are meant to fold.
- Some use ATP, some don’t.
- Their role is more diverse than was previously recognized. Some solely bind to conformational intermediates of client proteins, but some remain with proteins as they form their functional complex.
- They can work against you by protecting cancer cells. Mice that overexpress Hsf1, the transcription factor critical to producing heat shock proteins, develop more cancers than control mice. Mice that are knock-outs for Hsf1 develop fewer cancers, but are more susceptible to a host of other problems including neurodegenerative diseases.
- By helping mutated proteins to still fold normally, molecular chaperones can conceal genetic variations/mutations in protein-coding regions. If the organism is suddenly put under a lot of stress, though, the chaperones may be overtaxed, leading to the mutations suddenly becoming apparent. (Osmolytes, below, might do this too.)
The other class of helper proteins is the osmolytes, also sometimes referred to as chemical chaperones. These are compounds affecting osmosis, and they play a role in protecting cells from dessication and osmotic stress, heat, oxidative stress, high pressures, and other types of stress. They’re found in plants, animals, and microorganisms, and they are behind a) the creepy and amazing thermo-resilience of sea monkeys (apparently you can boil their eggs for an hour and many will survive) and b) cryptobiosis in plants (where they look completely dried out and dead but spring right back to life when they get some water.)
Trehalose is one of the more talked-about osmolytes – a pretty small and simple molecule that protects proteins from denaturation and stabilizes denatured proteins. There are dozens of others and they are super diverse in terms of structure. They include carbohydrates (sorbitol and myo-Inositol), amino acids (glycine and taurine), methylamines (betaine and TMAO) and urea (at a low concentration.)
It’s hard to say exactly how these guys work and a lot of smart people have a lot of different theories – possibly all are somewhat right and there are just a lot of different mechanisms.
Apparently a recent article has revitalized the field of osmolyte research – “Chemical chaperones assist intracellular folding to buffer mutational variations,” Bandyopadhyay, Nature Chemical Biology, 2012.
I posted excerpts from this article a while back, but need to give it more attention. I believe one big finding was that different osmolytes have totally different protein-stabilizing functions – proline and glycerol, for example, deal with surface mutations, whereas TMAO and trehalose deal with the hydrophobic protein core.