Cystic Fibrosis (CF) is one of the most common inherited childhood diseases, impacting 1:4,000 children born in the US (www.cff.org). One of the major breakthroughs in molecular medicine was the discovery by Francis Collins et al. in 1988, that the cause for CF in over 70% of patients was a single genetic mutation, an in-frame deletion of Phenylalanine 508 in the Cystic Fibrosis transmembrane conductance regulator gene (DeltaF508 CFTR). In contrast to wild type CFTR, the mutated ?F508 CFTR anion channel becomes misfolded, displays a conformational defect, and has little to no activity. Intense research in recent years indicates that the conformational defect caused by the F508 deletion not only impacts protein function, but to a major extent also protein interactions and post-translational modifications (PTMs), and that changes in the specificity and affinity of these interactions may drive the disease. Therefore, huge efforts are being made to develop new compounds that correct the conformational defect, but they are hampered by the fact that the conformational defect of ?F508 CFTR has not yet been fully characterized. Through the development of novel methods for in vivo structural characterization of proteins by mass spectrometry, investigation of post- translational modifications of CFTR, which influence protein conformation, and development of methods for identification of conformation-specific interactions, we aim to contribute to a better understanding of the conformational defect in CF and its impact on protein-protein interactions in this disease.
Cystic Fibrosis (CF) is one of the most common inherited childhood diseases, impacting 1:4,000 children born in the US (www.cff.org) and is caused by deletion of phenylalanine 508 in the CFTR protein. The deletion of F508 affects the 3-dimensional structure (conformation) of CFTR, alters how it is post-translationally modified, and how it interacts with other proteins, and ultimately leads to loss of its channel function. Through the development of novel methods for in vivo structural characterization of proteins by mass spectrometry and investigation of post-translational modifications of CFTR, we aim to understand the interrelationship between protein conformation, post-translational modification and protein-protein interaction in Cystic Fibrosis and enable the development of new strategies for therapeutic intervention.
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