CF Gender Gap May Be Caused by Estrogen-Protein Conflict

A new study published in the journal Science Advances sheds light on the molecular mechanisms responsible for the pathology of cystic fibrosis (CF), and may assist in the development of targeted therapies against the disease.

Researchers investigated the role of two proteins, KCNE3 and KCNQ1, and how they can contribute to the development of CF. The team proposes that the gender gap in CF lethality may be related to the interference of estrogen with these two proteins.

The study, titled “Structural basis for KCNE3 modulation of potassium recycling in epithelia,” was conducted by Brett Kroncke and colleagues from  Vanderbilt and Northwestern Universities.

Among the different proteins present in a cell, some are ion channel proteins, i.e., proteins that control the entry and exit of ions, such as potassium, magnesium, sodium or chloride, at the cell membrane. Cells communicate with each other by using these channels or “holes.”

The maintenance of ion flux is crucial for cell function and survival.  When this mechanism is impaired, several consequences may arise. In fact, CF is known to be associated with changes in the transport of certain ions, such as chloride, and is responsible for the abnormal accumulation of mucus, sweat and digestive fluids. Mortality among CF patients is frequently associated with lung infections, since bacteria take advantage of the excessive amount of mucus to grow on the surface of the lungs.

In their study, researchers studied the interaction between KCNE3 and KCNQ1. While KCNQ1 is an ion channel, KCNE3 binds to it and activates its function. The interaction between the two proteins was studied using a combination of laboratory techniques in order to understand the molecular dynamics, structure and similarity with other proteins.

KCNE3 regulates potassium transport, which influences chloride flux in organ tissues. In healthy subjects, the proper functioning of KCNE3 avoids the abnormal accumulation of fluids and mucus in the lungs, for instance. This led researchers to wonder if KCNE3 would be involved in the pathology of CF.

“This is an unusual case in biology where this accessory membrane protein binds to the ion channel and effectively turns the ion channel on,” said Wade Van Horn, the study’s co-author, in a news release. “That’s important especially in the trachea and epithelial tissues in your lungs”.

Researchers also used nuclear magnetic resonance, a technology that allows the observation of body tissues and organs with high resolution, and the analysis of the structure of several biomolecules, like ion channels on the cell membranes. This technique allowed researchers to discover that estrogen can negatively interfere with the interaction between KCNE3 and KCNQ1, leading to impaired function of KCNQ1 and, consequently, to the worsening of CF symptoms. This may explain why women with CF have more aggressive symptoms and a shorter life expectancy than men with the disease.

“This is really the golden era for the field of membrane protein structural biology. We are starting to really understand how these proteins are working together and what the architectures look like,” said Van Horn. “In the long term, a better understanding of how membrane proteins work will help to make CF and other diseases more easily treatable.”