# The Molecular Mechanisms of Polycystin-1 Proteolytic Cleavage in Kidney Health and Polycystic Kidney Disease

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $380,777

## Abstract

Project Summary/Abstract
The long-term goals of our laboratory are to understand biological functions of proteins encoded by polycystic
kidney disease (PKD) genes such as PKD1/polycystin-1 (PC1) and to determine PKD pathogenic pathways
when they are mutated. This proposal is build on our previous discovery of cis-autoproteolytic cleavage of PC1
at the GPS motif and its central role in regulating PC1's biogenesis, trafficking and function. Our central
hypothesis is that the GPS motif and the adjacent linker form a bipartite force-transduction module that
mediates key functions of PC1. The goal of this project is to use a combination of molecular, biochemical,
cellular, and biophysical methods as well as mouse models to dissect the role of the GPS-linker module in PC1
trafficking and function. Our Aims are: 1) Test the hypothesis that a tight association of the β1-strand within the
GPS is required for PC1 ciliary trafficking and function, and is disrupted by PKD1 mutations. We predict that
tight association of this β-strand within the GPS motif is required to enable PC1 to traffic to cilia and to induce
in vitro tubulogenesis in MDCK cells, and is disrupted by PKD1 mutations; 2) Test the hypothesis that high
rigidity and short length in the linker is required for PC1 ciliary trafficking and function, and is disrupted by
PKD1-associated mutations. We predict that the rigidity of the linker is required to enable PC1 to traffic to cilia
and to induce in vitro tubulogenesis in MDCK cells, and is disrupted by PKD1 mutations; and 3) Determine the
in vivo role of the GPS-Linker module for trafficking and function of PC1 in the mouse kidney during embryonic
and postnatal development. We will generate two new Pkd1 knockin mouse models affecting the GPS or the
linker respectively. We will compare their phenotypes and assess the expression, cleavage, and trafficking of
the mutant PC1 proteins in various developmental stages and nephron segments. These analyses should
provide mechanistic insights into how the two components of the module operate together to regulate both
forms of PC1 during embryonic and postnatal stages of development, and how their dysfunction might lead to
PKD. Overall, we anticipate that the proposed studies should lead to a better understanding of the fundamental
mechanisms that regulate PC1 function in kidney health and PKD, and might provide rationales for novel
strategies to target the disease by manipulating the force-transduction process in polycystin-1.

## Key facts

- **NIH application ID:** 10147879
- **Project number:** 5R01DK111611-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Feng Qian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,777
- **Award type:** 5
- **Project period:** 2017-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147879

## Citation

> US National Institutes of Health, RePORTER application 10147879, The Molecular Mechanisms of Polycystin-1 Proteolytic Cleavage in Kidney Health and Polycystic Kidney Disease (5R01DK111611-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10147879. Licensed CC0.

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