"Traditionally, researchers have defined how energy is utilized and transferred in the CFTR as a 'strict coupling' mechanism, meaning that one ATP molecule opens CFTR's gate, ions pass through and the ATP molecule is hydrolyzed and then the gate closes," Hwang said. "In this new model, we argue that the CFTR uses energy from ATP hydrolysis to carry out its function of chloride flow, but this coupling mechanism is more plastic than we thought and therefore could be subjective to manipulations by drugs such as Vx-770."
CFTR is part of a family of thousands of active transporter proteins called ABC proteins. Although CFTR may share many structural features with its ABC "cousins," as Hwang calls them, it has been unclear as to whether CFTR and its cousins may work in a similar manner.
The new idea of how the CFTR utilizes ATP to carry out its function may bear a broader implication because of the evolutionary relationship between CFTR and other ABC transporter proteins. It opens up a wide variety of therapeutic possibilities for other common diseases, such as cancer, heart disease and diabetes, Hwang said, since many other ABC proteins play critical roles in those human illnesses.
"It's taken years for scientists to solve this particular puzzle about the CFTR protein," Hwang said. "Our recent study provides evidence that these ABC transporter proteins and CFTR, a chloride channel, are two peas in a pod. Mother nature employs the same structural framework with just a little bit of modification to do two totally different things. From a basic science perspective, it's a big deal."
Using electrophysiology techniques available at MU's Dalton Cardiovascular Research Center, Hwang's lab studied the opening and closing, or "gating," of the CFTR at the single-molecule level. By measuring the electrical current that reflects directly the movement of chloride ions through one single CFTR channel as it opens and closes, Hwang's lab is able to monitor the activity of a single CFTR molecule in real time.
"Single-channel recording provides a unique opportunity to observe conformational changes in a single CFTR molecule in real time," Sheppard said. "It's exciting to think about how the new models proposed by Dr. Hwang and his colleagues explain the action of Vx-770 and other transformational drugs that target the root cause of cystic fibrosis."
Source: University of Missouri School of Medicine