Activation of Disease-Associated Polycystin-1 Mutants by Binding of Stalk-derived Agonist Peptides
- 1Department of Pharmacology and Computational Medicine Program, Bioinformatics and Computational Biology Program, University of North Carolina - Chapel Hill
Abstract
Polycystin-1 (PC1) functions as an atypical G-protein-coupled receptor (GPCR) with an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal (NTF) and membrane-embedded C-terminal (CTF) fragments. Mutations in PC1 are responsible for 85% of autosomal dominant polycystic kidney disease (ADPKD) cases. Activation of signaling by PC1 CTF has been shown to be allosterically mediated by a stalk tethered agonist (TA) and to be prevented by mutations of the stalk. Soluble, synthetic peptides derived from the PC1 stalk were also shown to re-activate signaling by a stalkless CTF mutant. Here, we have investigated the ability of selected stalk peptide agonists p9, p15 or p17 to re-activate signaling by PC1 CTF with ADPKD-associated missense mutations, G3052R or R3063C. Biochemical experimental data showed that each of the three stalk peptides was able to significantly reactivate signaling by the CTF-R3063C mutant. In contrast, signaling by CTF-G3052R could only be rescued by treatment with p17. In parallel, we employed peptide docking and novel Peptide Gaussian-accelerated Molecular Dynamics (Pep-GaMD) simulations to elucidate the binding conformations of p9, p15 and p17 to the PC1 mutants. The simulation findings were highly consistent with experimental data. Furthermore, Pep-GaMD revealed binding conformations of the agonist peptides and important low-energy conformational states of the PC1 CTF, as well as their critical residue interactions. Overall, our complementary approach provides important mechanistic insights into the re-activation of PC1 disease-associated mutants by stalk-derived peptide agonists. Such insights are expected to be valuable for the future design and development of peptide modulators targeting PC1 for an effective ADPKD therapeutic treatment.
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BibTeX
@misc{joshi2026activation,
title = {{Activation of Disease-Associated Polycystin-1 Mutants by Binding of Stalk-derived Agonist Peptides}},
author = {K. Joshi and B. S. Magenheimer and A. Haldane and Y. Zhang and Y. Miao and R. L. Maser},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.10.758211},
url = {https://www.biorxiv.org/content/10.64898/2026.10.10.758211v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Activation of Disease-Associated Polycystin-1 Mutants by Binding of Stalk-derived Agonist Peptides
AU - K. Joshi
AU - B. S. Magenheimer
AU - A. Haldane
AU - Y. Zhang
AU - Y. Miao
AU - R. L. Maser
PY - 2026
DA - 2026/10/10
PB - bioRxiv
DO - 10.64898/2026.10.10.758211
UR - https://www.biorxiv.org/content/10.64898/2026.10.10.758211v1
AB - Polycystin-1 (PC1) functions as an atypical G-protein-coupled receptor (GPCR) with an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal (NTF) and membrane-embedded C-terminal (CTF) fragments. Mutations in PC1 are responsible for 85% of autosomal dominant polycystic kidney disease (ADPKD) cases. Activation of signaling by PC1 CTF has been shown to be allosterically mediated by a stalk tethered agonist (TA) and to be prevented by mutations of the stalk. Soluble, synthetic peptides derived from the PC1 stalk were also shown to re-activate signaling by a stalkless CTF mutant. Here, we have investigated the ability of selected stalk peptide agonists p9, p15 or p17 to re-activate signaling by PC1 CTF with ADPKD-associated missense mutations, G3052R or R3063C. Biochemical experimental data showed that each of the three stalk peptides was able to significantly reactivate signaling by the CTF-R3063C mutant. In contrast, signaling by CTF-G3052R could only be rescued by treatment with p17. In parallel, we employed peptide docking and novel Peptide Gaussian-accelerated Molecular Dynamics (Pep-GaMD) simulations to elucidate the binding conformations of p9, p15 and p17 to the PC1 mutants. The simulation findings were highly consistent with experimental data. Furthermore, Pep-GaMD revealed binding conformations of the agonist peptides and important low-energy conformational states of the PC1 CTF, as well as their critical residue interactions. Overall, our complementary approach provides important mechanistic insights into the re-activation of PC1 disease-associated mutants by stalk-derived peptide agonists. Such insights are expected to be valuable for the future design and development of peptide modulators targeting PC1 for an effective ADPKD therapeutic treatment.
ER -