How (not) to fold a protein

Chaperones help proteins to fold correctly. Understanding the biological principles that guide these molecular assistants can teach us more about the many diseases in which proteins misfold and aggregate. A team of scientists at VIB-KU Leuven has now unraveled why chaperones favor certain protein regions for binding.

Even molecular structures like proteins can be quite complex. That’s why we have chaperones: proteins that assist other proteins to fold or unfold, for example during assembly or disassembly. This is of vital importance, as misfolded proteins would quickly accumulate and cause disease.

Generally speaking, chaperones tend to be promiscuous, interacting with a broad range of different proteins. However, most chaperones do show a preference for certain protein segments, which helps them to shield those regions that are normally buried within the folded protein.

Over the past few decades, many researchers have tried to determine the general binding patterns for molecular chaperones, but why they prefer certain sequences has remained unclear.

Aggregation and folding

A team of researchers led by Frederic Rousseau and Joost Schymkowitz (VIB-KU Leuven) has found that the interaction between chaperone and protein is the result of evolutionary constraints on protein structure:

“While acidic residues are least likely to aggregate, they are also difficult to incorporate into a large 3D protein structure,” says Rousseau. “Basic residues on the other hand are more compatible, but they may lead to aggregation during folding.”

Schymkowitz: “In order to favor proper folding over aggregation, aggregation-prone regions are systematically flanked by charged residues that disfavor aggregation. We were able to demonstrate that acidic and basic residues are fundamentally different when it comes to their ability to achieve this feat.”

The team showed how one particular chaperone, called Hsp70, is structurally adapted to achieve this. “We show that Hsp70 is adapted to bind regions that are capped by so-called ‘basic gatekeepers’. As such, Hsp70 compensates for the fact that they may not be able to prevent aggregation on their own,” explains Bert Houben, PhD student in the lab of Rousseau and Schymkowitz.

Evolution at work

The team’s findings suggest that the co-evolution of basic residues and chaperones allowed for an explosion of structural variety in the protein universe.

Houben: “Apart from the evolutionary implications, our findings expose universal, fundamental rules governing protein architecture and folding. This information can help us to better understand the mechanisms underlying protein misfolding disorders.”

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Autonomous aggregation suppression by acidic residues explains why chaperones favour basic residues
Houben et al. EMBO J 2020