The cell addresses the folding problem with a large collection of helper proteins that work in teams, with a 'head helper,' chaperone, surrounded by 'assistant helpers,' co-chaperones. Without these helper proteins, healthy CFTR cannot attain its active form, and the defective, diseased forms of CFTR require this assistance even more. Despite this extra help, there are still patients who do not benefit because the CFTR mutants cannot manage.
We have previously found that healthy CFTR protein requires assistance from the chaperone Hsp90. Without Hsp90, the healthy CFTR protein folds as poorly as the most common diseased variant, F508del-CFTR. Hsp90 is like a spider in a web of chaperones and co-chaperones, all of which help regulate and improve the function of Hsp90.
Together with the laboratory of Professor Georgios Karras in Houston (USA), we have now discovered that yet another chaperone is required for the folding of CFTR, namely Hsp70. Furthermore, the assistance of Hsp90 and Hsp70 seems to be specific to the CFTR protein, as family members of the CFTR protein are much less dependent on Hsp90. We have also determined that Hsp90 and Hsp70 primarily bind to the N1 portion (the purple section in the image). This is exactly where the F508del mutant is located. N1 appears to be the foundation of a well-functioning CFTR channel, and many mutations in N1 lead to the strongest assistance from the helper proteins and yet the most severe defects.