Mechanism of tethered agonist-mediated signaling by polycystin-1
Abstract
Mutations of polycystin-1 (PC1) are the major cause (85% of cases) of autosomal dominant polycystic kidney disease (ADPKD), which is the fourth leading cause of kidney failure. PC1 is thought to function as an atypical G protein-coupled receptor, yet the mechanism by which PC1 regulates G-protein signaling remains poorly understood. A significant portion of ADPKD mutations of PC1 encode a protein with defects in maturation or reduced function that may be amenable to functional rescue. In this work, we have combined complementary biochemical and cellular assay experiments and accelerated molecular simulations, which revealed an allosteric transduction pathway in activation of the PC1 C-terminal fragment. Our findings will facilitate future rational drug design efforts targeting the PC1 signaling function.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 06, 2022
- Source ID
- 10.1073/pnas.2113786119
Entities
People
- Brenda S. Magenheimer
- Ericka Nevarez Munoz
- Robin L. Maser
- Shristi Pawnikar
- Yinglong Miao
Organizations
- National Institutes of Health
- United States Department of Defense
- University of Kansas