Jeffrey Beekman - Improving CF Treatment
Ineke Braakman - Protein Folding

Determined to Defeat CF

Ineke Braakman, Utrecht, February 28, 2018

Our Quest for Helping Hands for CFTR We consume proteins because we need the building blocks of those proteins (amino acids) to continually create new proteins.

This occurs in all cells of our body, where proteins perform almost all the work. They can only perform this work when they have attained the correct shape, and this is impossible without assistance.

Cystic Fibrosis is caused by a defect in the large and complex protein CFTR. In our project, we are searching for the helper proteins that assist CFTR in attaining its active form.

Proteins are like strings of beads that fold into a specific 3D shape. Only when CFTR has the correct shape (as shown in the picture) can it perform its function, which is transporting salt out of the cell.

CFTR is a chain of 1480 beads. It's almost unimaginable that this protein machine consists of just a single chain, but it does. The beginning and end of the chain are indicated.

It helps that CFTR initially folds into 5 components. Then, it becomes a chain of 5 interconnected puzzle pieces (T1, N1, R, T2, N2, as shown in the drawing) that need to fit together. But even then, this process isn't achievable without assistance, and CFTR is just one of approximately 20,000 different proteins in our body that require folding.

The cell tackles this folding problem with a large collection of helper proteins that work in teams. Without these helper proteins, CFTR cannot attain its active form, and the defective, diseased forms of CFTR need this assistance even more urgently.

We've already found that the healthy CFTR protein is only healthy thanks to the assistance of a main helper protein, Hsp90. Without Hsp90, CFTR folds as poorly as the most common sick variant, F508del-CFTR. Hsp90 is like a spider in a web of helper proteins, all of which help regulate and improve Hsp90's function.

Acceleration in the Search for CFTR Helper Proteins Our quest for CFTR helpers has recently received a significant boost. In Cambridge (USA), a young researcher, Dr. Georgios Karras, who will soon start his own group, is working. In the lab where he currently works, a method has been established to test almost all possible helpers in the cell (and certainly all helpers in the "Hsp90 team") in a short time to see if they bind to CFTR, parts of CFTR, or proteins related to CFTR.

We have done preparatory work for this, and we expect that Dr. Karras will soon be able to tell us exactly which helpers do and do not bind to CFTR and whether this is unique or if they also bind to CFTR relatives. Like all investigations in biology, this is still only a "partial result," and we need to confirm these results with another method. Still, with Georgios's results, we can hopefully conclude our quest and focus entirely on examining the precise effect of each binding helper on CFTR folding.