Christopher Ward

Christopher Ward
Associate Professor, Nephrology and Hypertension
University of Kansas Medical Center

 

 

Delineate the X-ray structure of CU062, a polycystin-1 ligand (2018-19)

Autosomal dominant polycystic kidney disease is a common life threatening disease and the commonest genetic cause for renal failure. Conservative estimates put its cost to society in the range of 4-10 billion dollars per year. Insight into the structure and function of polycystin ligands is vital if rational targeted therapies are to be developed. CU062 is a protein which interacts with the PKD domains of the polycystin-1 protein (PC1). PC1 is the product of the polycystic kidney disease type 1 gene (PKD1). When one allele of the PKD1 gene is mutated in humans it gives rise to autosomal dominant polycystic kidney disease, where many small cysts in the kidney slowly dilate and destroy the kidney. On average an individual with PKD1 will develop renal failure at the age of 54 yrs. The disease is common affecting 1:800 individuals.

CU062 was discovered by analyzing urinary exosomes in PKD individuals where it was shown to be decreased in abundance. Follow up analysis shows that it has a high affinity for the PC1 protein. CU062 is a small secreted protein of 42kDa which belongs to a family of proteins, described in PFAM as a ‘Domain of Unknown Function’ (DUF4571). CU062 is interesting in that it is predicted to be secreted and to be very leucine rich.

We wish to gain an insight into the biology of CU062 by determining its 3D structure. We believe this will give us insight into the mechanism of its interaction with PC1.