Sneaky Chaperones in our War Against Bacterial Infection

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I guess most of you know about the ‘central dogma’ of science of DNA-> RNA->Protein. But what happens next? You get a beautiful (in my opinion) folded functional protein that can do a mind-boggling array of things… and that’s not even the end of the story.

Proteins in our body do almost everything from allowing neural connections to repairing DNA to prevent cancers. These proteins although incredibly powerful can be put under pressure and become damaged; if this does happen then cells have a range of response mechanisms, one of which is to make even more proteins. The proteins I want to talk about are called molecular chaperones because they pretty much hold the hand of and look after proteins that become unfolded within the cell to prevent them from: sticking together (aggregating), getting chopped up by proteases or being bound by other molecules like protons that damage the protein.

Chaperones (like most other things) have been best studied in the bacteria E.coli so I’m going to explain how bacteria have formed a fined-tuned and rapid response to proteins becoming at risk. Chaperones are mostly know in their role during de novo (from start) folding, when a protein is transcribed by the ribosome and a chaperone binds to aid in its transportation to the place it’s needed or localised to in the cell and allows it to find its native structure. Certain chaperones however have evolved specifically to deal with cellular stress, especially in gram negative bacteria such as E.coli as it has a cellular envelope, or periplasm, between its inner and outer membranes which is very susceptible to environmental changes.

Bacterial can get into our body in a number of ways one of which is if it is in/on our food (you 5 ‘minute’ rule people), bacteria that infect us this way are known as enteric, including E.coli. Our main defence against these bacteria is our stomach acid which is usually at pH 3. As we known bacteria are tricky blighters and have lots of ways they can become resistant to most antibiotics we throw at them, but they even have a way to survive in our stomach acid!

E.coli and other bacteria have a molecular chaperone called HdeA which is activated on acid-stress and prevents protein unfolding in the cells to help them survive. HdeA is translated in cells under normal conditions and happily sits as a dimer (two full protein chains bound together) until the bacterium is exposed to acid. It then monomerises and partially unfolds so it can bind a wide range of essential proteins in the periplasm that would otherwise irreversibly misfold or interact with the excess protons and if these essential proteins are lost the cell dies. So HdeA holds the proteins until the coast is clear and the pH reaches normal levels again in the intestine, where they can refold and carry on with their business.

It’s a clever little system which makes fighting bacterial infection that bit harder, and if things weren’t tricky enough…it has a twin. HdeB is also a chaperone which has the exact same structure but doesn’t work at pH 2-3, it works at pH 4. So if you haven’t eaten in a while and your stomach acid pH goes up slightly E.coli can still find its way round our body’s defences.

Although the system helps bacteria evade our defences, now that we know about it, we may be able to double bluff them and hack their own survival mechanisms with molecules or new therapeutics. In the war between man and bacteria the more we know about their tactics the better we can plan our attacks against them.

Julia Rose

Reference:
Dahl JU, Koldewey P, Salmon L, Horowitz S, Bardwell JC, & Jakob U (2015). HdeB Functions as an Acid-protective Chaperone in Bacteria. The Journal of biological chemistry, 290 (1), 65-75 PMID: 25391835

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