Cystic fibrosis (CF) is a fatal genetic disorder caused by abnormal function of the cystic fibrosis membrane conductance regulator (CFTR). CFTR is an ATP-binding cassette (ABC) transporter expressed in the transport epithelia and plays a central role in the membrane transport system. Therefore, CFTR is involved in many respiratory and digestive diseases, including CF, chronic obstruction (COPD) and chronic pancreatitis.
CF is common in Caucasians. Deletion of phenylalanine at position 508 (ΔF508) in Nucleotide Binding Domain 1 (NBD1) is the most common CF-associated mutation and causes defects in CFTR trafficking to the plasma membrane (class II). Several Japanese-specific CF-causing mutations have been also identified in NBD1. The NBD1 molecular instability should lead to the CFTR protein degradation causing the classⅡtrafficking defect.
In this work, using molecular dynamics simulations, we investigated the molecular fluctuation of NBD1 with and without the disease-associated mutations and discuss about the pathophysiological mechanisms of the Japanese CF.