Molecular mechanisms of mucin barriers and defects during cystic fibrosis
The gel forming mucins, MUC2 (intestine), MUC5AC (airways, stomach), MUC6 (stomach) and MUC5B (airways), form a protective epithelial barrier tightly regulated. They all have large sizes with heavily glycosylated mucin domains in the central part. The N- and C-terminal regions are important for oligomerization.
Cystic fibrosis (CF) is an inherited disease where the expression of mucins is abnormal. Main clinical symptoms are from the lungs, pancreas and intestine. Pulmonary disease is the major cause of morbidity and mortality. CF is caused by a nonfunctional chloride and bicarbonate ion channel (CF transmembrane regulator, CFTR).
One of the goals of the project is to on molecular level understand how the extremely viscous mucus is formed in CF. Solving this problem will give big advantages in the treatment of the disease and may result in a “simple” and common therapy for more than 1900 pathogenic mutations.
N-terminal mucin domains are expressed in chinese hamster ovary cells. The secreted recombinant mucin is purified from culture medium by anion exchange chromatography and structurally analyzed by transmission electron microscopy, single particle image processing and other computer based techniques.
Our results have revealed the mechanism behind how MUC2, through its N-terminal, builds up a protective mucus layer in intestine. Due to high evolutionary similarities we now use the above knowledge performing structural studies on MUC6 and MUC5AC and MUC5B.
Novel data indicate that the mucus gel of MUC2, MUC6, MUC5AC and MUCB is assembled differently. We have so far , on MUC2 forming netlike like structures due to trimerization of its N-terminal domain. Understanding of tissue specific properties of the different mucus gels is expected to be beneficial for drug design developing selective treatments. Although focusing on CF, our research likely also will contribute to the understanding of other diseases with altered mucus expression.
The project is performed in collaboration with Gunnar Hansson´s mucin biology groups in Gothenburg.