Protein origami and the cell's folding masters

Just as a misshapen key can't open a lock, the proteins in our cells need to have the correct 3D shape to function properly. And defects in a protein's structure can cause diseases.

Proteins are initially stitched together inside cells by large molecular machines called ribosomes, which "grow" the protein by adding a sequence of small amino acid building blocks one after the other. This creates linear chains, which fold, origami-like, into the correct 3D structure.

However, while origami involves folding a fully made sheet of paper, a protein chain starts to fold while it's still being stitched together. This poses challenges, as regions of a protein that need to end up in close proximity in the final structure aren't always synthesized at the same time.

One way evolution has tried to solve this challenge is through chaperones—specific proteins that help other proteins fold correctly, including while they're being made. But despite chaperones' importance in determining a protein's structure and function, researchers still don't fully understand how they work.

"There's so much we still need to learn about how chaperones help proteins fold," says David Balchin, who leads the Crick's Protein Biogenesis lab. "A particular mystery my lab has been focusing on is the series of events that occurs as the nascent protein chain starts to emerge from the ribosome itself, and how chaperones might stop it getting tangled and misfolded."

Folding choreography

Recently, researchers in Balchin's lab have used a range of techniques to map out in exquisite detail, how particular chaperones coordinate their action during protein synthesis in bacteria.

They discovered that, as a new protein chain emerges from a ribosome and reaches about 100 amino acids in length, it's grabbed by a chaperone called Trigger factor.

As the protein continues to emerge, Trigger factor performs some clever choreography, attaching itself to regions that have yet to finish folding, and detaching from those that are nearly fully folded. Through this dance of binding and unbinding, Trigger factor shields partially folded regions from the rest of the cellular environment, which may help prevent mistakes forming.

Balchin's team has also started to reveal how this shielding effect helps coordinate other chaperones. When Trigger factor first binds to an emerging chain, it prevents other chaperones from binding. But as the chain grows, some regions escape from Trigger factor and new chaperones can then engage in the folding choreography.

"We're carefully starting to dissect the series of events that allow chaperones to coordinate protein folding as a chain emerges from a ribosome, revealing how features of proteins that are being created in real time dictate the complex and dynamic coordination of chaperones," says Balchin.

Understanding how living organisms have evolved mechanisms to enable protein folding during synthesis is important to gain insight into how the molecular machinery of life works correctly. And it could, one day, identify ways to manipulate proteins to develop treatments for different diseases.

Provided by The Francis Crick Institute