Understanding Polycystin-1 Structure and Function: Mechanistic Clues from the Adhesion Class of G Protein-Coupled Receptors
Abstract
This project addresses the Fiscal Year Peer Reviewed Medical Research Program Topic Area of polycystic kidney disease (PKD). Autosomal dominant polycystic kidney disease (ADPKD) is the most common, potentially lethal inherited kidney disease, affecting nearly 1 in every 400-1,000 individuals. Both of the kidneys of affected individuals develop numerous small cysts, which progressively enlarge, and ultimately lead to the loss of renal function in half of those affected. In the United States, approximately 8% of all cases of renal failure requiring hemodialysis or transplantation are due to ADPKD. Currently, there is no cure for ADPKD. In 85% of cases, ADPKD is caused by the loss of function of a protein named polycystin-1 (PC1). PC1 is a very large, complex protein embedded within the outer plasma membrane of most cells, which has been implicated in multiple cellular functions based on experimental observations. Among these is an ?adhesion function,? performed by the portions of PC1 that protrude from the cell surface, which is thought to mediate interactions between cells or between a cell and the extracellular matrix or ?surface? on which it resides. The intracellular end of PC1 (i.e., its C-tail) is thought to perform a ?signaling function? via its ability to directly interact with and to initiate the activity of heterotrimeric G proteins. Once activated, heterotrimeric G proteins will initiate a signaling cascade by binding to their ?effectors,? which are usually enzymes, and either promoting or inhibiting their functions, ultimately leading to specific cellular responses or functions. The membrane-embedded proteins that typically bind and activate heterotrimeric G proteins are called G protein coupled receptors (GPCRs) and are responsible for communicating signals from the extracellular environment to the interior of the cell. Unfortunately, neither the adhesion or signaling function of PC1 nor how the loss of either contributes to the development or progression of ADPKD are well understood. A recent study looking at the effect of an ADPKD mutation within the portion of the PC1 C-tail that binds and activates heterotrimeric G proteins showed that the mutation prevented G protein signaling in cultured cells and led to development of PKD in a mouse model. This work strongly suggests that signaling via heterotrimeric G proteins is a critical, authentic function of PC1, important for preventing the formation of renal cysts, and further emphasizes a critical problem in the ADPKD field: that the functional outcomes, associated disease consequences, and the molecular mechanism for the regulation of PC1-mediated heterotrimeric G protein signaling are completely unknown. We have observed that PC1 shares a number of similarities in regard to both its structure and its proposed functions with a group of GPCRs that are involved in cell adhesion (i.e., the Adhesion class). Importantly, the molecular mechanism responsible for regulating the activation of heterotrimeric G proteins by adhesion class GPCRs was recently discovered. We hypothesize that PC1 utilizes a similar mechanism to modulate its G protein activation, which will be tested by the studies proposed in Specific Aim 1. In Aim 2, we propose to generate new cultured cell lines that will enable us or other investigators to perform future studies designed to further elucidate the mechanism and functions of PC1-mediated G protein signaling. The major goal of this proposal is to test a new paradigm, inspired by the functional and structural similarities between PC1 and the cell adhesion class of GPCRs, in order to determine the mechanism by which PC1-mediated G protein signaling is regulated. In the short term, completion of these aims is expected to provide evidence supporting our hypothesis and to generate compelling preliminary data and crucial reagents that will form the basis of a future National Institutes of Health (NIH) R01 application seeking t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710301
Entities
People
- Robin L. Maser
Organizations
- United States Army
- University of Kansas Medical Center