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Proteins are central to (nearly) all cellular processes. Their function depends on proper folding, a process guided by their amino acid sequence and fine-tuned by post-translational modifications. When folding goes wrong, proteins may be degraded or accumulate as aggregates, leading to diseases.

This thesis focuses on two medically relevant proteins: the cystic fibrosis conductance regulator (CFTR) and Janus kinase 2 (JAK2). CFTR is an ion channel essential for salt homeostasis. Mutations that impair its folding and activity cause cystic fibrosis. In this study, I investigated the open and closed states of CFTR in cells using biochemical approaches, and identified a proteolytic phenotype in a mutant mimicking the open conformation. I then characterized the mechanism of action of a novel corrector compound, X307810, which rescues misfolding of the (most prevalent) F508del-CFTR mutant with efficacy comparable to approved correctors but through a distinct mode of action.

Next, I explored the nature and functional role of CFTR N-linked glycans, demonstrating that while complex glycosylation does not affect CFTR folding or function, it influences the density of CFTR at the plasma membrane.

In the final part of this work, I turned to JAK2, a cytosolic tyrosine kinase central to hematopoiesis and immune signaling, where dysregulated activity drives myeloproliferative neoplasms. I investigated O-GlcNAcylation as a potential regulatory mechanism and found no evidence of modification within the kinase domain, opening for future research directions.

Together, my findings deepen the understanding of CFTR folding and pharmacological rescue, clarify the role of complex glycosylation in channel regulation, and evaluate JAK2 post-translational regulation, with implications for therapeutic development.