Chaperones are essential for proper protein folding. Understanding the biological principles of chaperone-protein binding can help prevent toxic protein aggregation, which occurs in a wide range of disorders. A Leuven research team now shows how the preference of chaperones for basic residues came about.
Chaperones tend to be promiscuous in their binding, which allows them to assist with the folding of a broad range of different proteins. However, most chaperones do show a preference for hydrophobic segments so they can shield aggregation-prone regions that should normally be buried in the native state of the protein.
Over the past few decades, many researchers have tried to determine the general binding patterns for molecular chaperones, but why they prefer basic/hydrophobic sequences has remained unclear.
Aggregation and folding
A team of researchers led by Frederic Rousseau and Joost Schymkowitz (VIB-KU Leuven) found that the preference of the protein quality control machinery for basic residues is a consequence of fundamental structural and evolutionary constraints on globular structure.
“While acidic residues are the most efficient aggregation inhibitors, they are also less compatible with globular protein structure,” says Rousseau. “Basic residues on the other hand are more compatible with globular structure, but they are not efficient enough to fully suppress aggregation.” In other words, while acidic residues allow for chaperone-independent control of aggregation, their usability is structurally limited.
In come chaperones, explains Schymkowitz: “In order to favor native 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 a chaperone like Hsp70, with a bias towards basic residues, is structurally adapted to prioritize aggregating sequences whose structural context forced the use of the less effective basic residues. “We show that Hsp70 is adapted to bind regions that are capped by ‘basic gatekeepers’. As such, Hsp70 compensates for their poorer intrinsic ability to inhibit aggregation,” 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 proteostatic disorders, and to better design protein sequences and expression conditions for bioproduction.”
The Switch Laboratory was supported by grants from the European Research Council under the European Union's Horizon 2020 Framework Programme ERC Grant agreement 647458 (MANGO), the Flanders institute for biotechnology (VIB), the University of Leuven (“Industrieel Onderzoeksfonds”), the Funds for Scientific Research Flanders (FWO), the Flanders Agency for innovation by Science and Technology (IWT, SBO grant 60839) and the Federal Office for Scientific Affairs of Belgium (Belspo), IUAP, grant number P7/16.