# Structures and Mechanisms of Polycystic Kidney Disease Proteins

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $343,125

## Abstract

Project Summary
Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder with various extrarenal
manifestations, including life-threatening complications involving the cardiovascular system. ADPKD
represents one of the most common genetic diseases, with over 600,000 cases in the United States and about
12.5 million cases worldwide. ADPKD is caused by mutations in PKD1 or PKD2 genes that encode two
founding members of the functionally enigmatic polycystin family of membrane proteins. Structurally, PKD1 is
an 11-transmembrane spanning receptor-like protein with a remarkably large extracellular N-terminus that is
thought to participate in the detection of unknown extracellular stimuli or ligands. PKD2 is a transient receptor
potential (TRP) channel that shares a similar architecture with well-characterized tetrameric voltage-gated ion
channels. PKD1 and PKD2 co-assemble into a heteromultimeric receptor/ion channel complex at primary cilia,
likely responding to mechanical force of fluid shear and/or chemical stimuli. Currently, structural information of
polycystin proteins is only available for several individual soluble domains despite the urgent need for
structures of a complete receptor or channel to inform physiological and pharmacological studies and to guide
rational design of effective strategies to treat ADPKD patients. Moreover, the basic biophysical properties of
polycystin proteins and how these properties are altered in disease-associated mutations remain largely
unknown. Here, we propose two specific aims that will use a range of biophysical and structural approaches to
address these fundamental questions, which are of both basic and translational significance. Our preliminary
data include a structure of PKD2 in the closed conformation in lipid nanodiscs at 2.9Å resolution. We have also
prepared a construct that includes the EF hand domain and obtained preliminary EM data that are expected to
reveal similar resolution structures of the open and/or desensitized states in the presence of regulatory cellular
factors such as calcium and PIP2. These structures form the basis for precisely designed mutagenesis
structure-function studies. Successful outcome will provide a detailed view of PKD2 in multiple functionally
important states and establish how unique structural features of PKD2 correlate with its physiological functions.
The primary goal of Aim 2 is to characterize the biophysical properties of PKD1, PKD2, and the PKD1/PKD2
complex, with the longer-term goal of providing relevant structural information. Toward this goal, our
preliminary data include preparation of relevant proteins in biochemically tractable states. Successful outcome
will clarify the currently obscure mechanistic roles of these disease-associated channel proteins, provide a
basis to understand the impact of disease-associated mutations, and inform future efforts to develop novel
therapeutics.

## Key facts

- **NIH application ID:** 9982295
- **Project number:** 5R01DK110575-05
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Erhu Cao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,125
- **Award type:** 5
- **Project period:** 2016-09-16 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982295

## Citation

> US National Institutes of Health, RePORTER application 9982295, Structures and Mechanisms of Polycystic Kidney Disease Proteins (5R01DK110575-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9982295. Licensed CC0.

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