# Structural Mechanisms of Polycystic Kidney Disease Proteins

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $681,496

## Abstract

Project Summary
The human polycystin family of membrane proteins consists of versatile cellular censors classified as PKD1-like
11-transmembrane (TM)-spanning receptors (PKD1, PKD1L1, PKD2L2, and PKDREJ) and PKD2-like 6-TM-
spanning cation channels (PKD2, PKD2L1, and PKD2L2). PKD1 and PKD2 were first identified as the two cul-
prits that are mutated autosomal dominant polycystic kidney disease (ADPKD). ADPKD is the most common
monogenic disorder and fourth leading cause of kidney failure. PKD1 and PKD2 assemble into a heteromeric
receptor/ion channel complex at primary cilia in the kidney where they sense mechanical and/or chemical stimuli
and contribute to the development and maintenance of the exquisite tubular architecture of nephrons. PKD2
additionally functions co-dependently with PKD1L1 at vertebrate embryonic node cilia to mediate Ca2+ influx,
which initiates a transcriptional program that determines left-right asymmetry of internal organs and the vascu-
latures. Mutations in PKD1L1 lead to development of heterotaxy, biliary atresia (BA), and congenital heart de-
fects (CHD). PKDREJ and PKD2L2, two understudied polycystin members, likely participate in Ca2+ signaling in
sperms and are crucial in male reproduction. Polycystin proteins have been historically studied using human
genetics and functional analyses in model organisms, but we still do not fully understand their assembly princi-
ples, structure-function relationships and channel properties. Furthermore, kidney cells secrete PKD1/PKD2 into
urine in form of membrane-bound extracellular vesicles (EVs), sparking intense efforts to translate total urinary
EVs as a non-invasive biomarker for prognosis/diagnosis of ADPKD but with limited success due to their inherent
impurity. In this application, our goals are to: 1) determine structures and stoichiometry of the PKD1/PKD2,
PKD1L1/PKD2, and PKDREJ/PKD2L2 complexes and define their channel properties that underlie their diverse
roles in a range of sensory processes; 2) develop PKD1/PKD2-containing EVs into an ADPKD biomarker, profile
their molecular cargo, and determine a PKD1/PKD2 structure embedded in EVs. Overall, our holistic and com-
parative studies of various polycystin complexes 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 to treat ADPKD, BA, and CHD.

## Key facts

- **NIH application ID:** 10872659
- **Project number:** 1R01DK139541-01
- **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:** 2024
- **Award amount:** $681,496
- **Award type:** 1
- **Project period:** 2024-07-22 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872659

## Citation

> US National Institutes of Health, RePORTER application 10872659, Structural Mechanisms of Polycystic Kidney Disease Proteins (1R01DK139541-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10872659. Licensed CC0.

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