The kidney senses and responds to physiological changes, such as pH, ionic strength, pressure, and nutrient levels. Sensing is mediated by a coupled sensor/ion channel complex called the Polycystic Kidney Disease Channel, which is composed of two subunits, the PKD1 (the primary sensor) and PKD2 (the channel). Autosomal dominant PKD mutations are amongst the most common monogenic disorders and lead to untreatable end-stage renal failure.
To learn how this system works and is adversely affected by PKD mutations, Cao, Shen, and colleagues determined a high-resolution cryo-EM structure of the PKD2 channel in lipid nanodiscs. This breakthrough accomplishment provided considerable insight into how the PKD2 channel functions. The result was also the first time that cryo-EM was used to determine a high-resolution membrane protein structure at the University of Utah. Finally, it was one of the first membrane protein structures determined within a native-like lipid nanodisc environment, a technology that Cao helped to pioneer.
TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Gao Y, Cao E, Julius D, Cheng Y. Nature. 2016 Jun;534(7607):347.
The structure of the polycystic kidney disease channel PKD2 in lipid nanodiscs. Shen PS, Yang X, DeCaen PG, Liu X, Bulkley D, Clapham DE, Cao E. Cell. 2016 Oct;167(3):763.
Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels. Zheng W, Yang X, Hu R, Cai R, Hofmann L, Wang Z, Hu Q, Liu X, Bulkley D, Yu Y, Tang J, Flockerzi V, Cao Y, Cao E, Chen XZ. Nature Communications. 2018 Jun;9(1):2302.
Press Releases and Media:
University of Utah Health: “Unmasking a “Silent Killer”: A Culprit Behind Polycystic Kidney Disease”