Targets for cystic fibrosis therapy: proteomic analysis and correction of mutant cystic fibrosis transmembrane conductance regulator

Abstract

Proteomic analysis has proved to be an important tool for understanding the complex nature of genetic disorders, such as cystic fibrosis (CF), by defining the cellular protein environment (proteome) associated with wild-type and mutant proteins. Proteomic screens identified the proteome of CF transmembrane conductance regulator (CFTR), and provided fundamental information to studies designed for understanding the crucial components of physiological CFTR function. Simultaneously, high-throughput screens for small-molecular correctors of CFTR mutants provided promising candidates for therapy. The majority of CF cases are caused by nucleotide deletions (DeltaF508 CFTR; >75%), resulting in CFTR misfolding, or insertion of premature termination codons ( approximately 10%), leading to unstable mRNA and reduced levels of truncated dysfunctional CFTR. In this article, we review recent results of proteomic screens, developments in identifying correctors for the most frequent CFTR mutants, and comment on how integration of the knowledge gained from these studies may aid in finding a cure for CF and a number of other genetic disorders.

Figure 1. Cystic fibrosis transmembrane conductance regulator and location of the most frequent mutations

Red regions indicate the nucleotide binding domains (NBD1 and NBD2) and the green region is the regulatory (R) domain. The black rectangle represents the ΔF508 mutation and ‘X’ represents premature termination codons.