Chaperones aren’t just the awkward adults at your high-school dance, but also a type of protein that University faculty are starting to better scientifically understand.
Biology Prof. Ursula Jakob and a team of collaborators comprise a study that examines chaperone protein Hsp33, which the team specifically investigated in bacteria. The study has been going on over the course of the past four years, and they recently had their paper published in Cell, a renowned biology journal.
The function of chaperone proteins is to help other proteins function, and until Jakob’s study, the way in which Hsp33 work in bacteria was unknown. She said the implications for studies on such proteins are crucially important, since all modern life relies on the function of proteins to carry out basic processes in cells to survive.
Jakob said when any cell in any organism encounters stresses like a fever or viral infection, its proteins start to denature, or lose the structure that they need to function properly.
“Not only do they lose activity, but what’s worse, they start to want to form aggregates,” Jakob said. “This is very toxic for the cell. The reason it’s so toxic is it’s irreversible.”
Jakob said this conglomeration is similar to an egg boiling, beginning in a liquid form before turning solid through the boiling process. Jakob and her team discovered how Hsp33 prevents protein inside bacteria cells from hardening when under attack by stressors, specifically bleach.
“This is important because we produce bleach in our body,” Jakob said. “Our white blood cells produce bleach to kill off bacteria.”
Jakob and her team found that when bleach activates Hsp33, it actually unfolds, losing some of its structure before interacting with other proteins.
“In contrast to all the other proteins which unfold and lose their function, Hsp33 needs this unfolding to gain its function,” Jakob said. “This is very contrary to what has been in the textbooks for many, many years.”
Until this study, it was a well-known theory that proteins lose function when they lose their structure, according to Jakob. However, because Hsp33 does the opposite, the new findings seem to be a revolutionary exception to the rule, she said.
“(Hsp33) uses the flexibility it gets because it loses part of its structure to really embrace and mold itself around other proteins that are unfolding and thus preventing them from interacting with other unfolding proteins and forming those aggregates,” Jakob said.
Jakob explained that the second part of the study involved discovering what happens once the stressor is gone, and how the partially unfolded proteins regain their structure so they can again perform functions required for the bacteria to live.
“Ideally, the client needs to gain back its structure to function again, because we want to survive the stress condition, not just endure it,” Jakob said.
Jakob and her team found that when the stressful conditions dissipate, Hsp33 pulls the client protein farther apart. This conformational change allows the client protein to be available for another class of chaperone proteins that will refold them to their active state, according to Jakob.
“In general, it’s a mechanism for how bacteria defend themselves against stress — stress that they encounter when they invade us,” Jakob said. “It’s a very clever strategy these bacteria have developed because it’s so instantaneous.”
Though chaperone proteins like Hsp33 are found mainly in bacteria, they also appear in some unicellular, eukaryotic parasites like Trypanosoma that causes sleeping sickness, Jakob said. Ultimately, she said her team hopes to use their findings for drug design against such diseases.
“If we understand how they defend themselves, we can understand how to attack them better,” she said.
Dana Reichmann, research fellow in the Department of Biology and another author of the paper, further explained the significance of the discoveries regarding Hsp33.
“We knew it’s important for bacteria, but we didn’t really know the mechanism for the protection,” Reichmann said.
Reichmann said Hsp33 acts like Play-Doh in its flexibility, binding to the proteins at risk from stress in order to protect them.
“There is really nice structural interplay with the chaperones and the substrate … They affect the conformation of each other which enables further release of the protein,” Reichmann said.
Reichmann also highlighted that before their research, it was unclear how Hsp33 acted without any added Adenyl triphosphate energy — the primary energy source produced and used by the human body.
“It’s really one of the first chaperones which are not ATP-dependent chaperones,” Reichmann said. “Up to now, it was unclear how these type of chaperones were working … it brings another mechanism to different types of chaperones, not necessarily the ones we know.”
Reichmann said there are homologous proteins found in plants, and more studies relating to Hsp33 and similar chaperone proteins are in the works, noting that this study is just the beginning.
“To look at chaperones and parasites and look at how we can target them … this will be really cool to study,” she said.