Activation of Disease-Associated Polycystin-1 Mutants by Binding of Stalk-derived Agonist Peptides
Year: 2026
Type: preprint
Abstract: 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. Visual Abstract Structural dynamic models are presented for binding of novel synthetic, soluble peptide agonists and associated activation of disease-associated Polycystin-1 mutants through a combination of complementary cellular signaling assays and accelerated molecular simulations. The p17 peptide derived from the first 17 residues of the protein stalk tethered agonist is shown here.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: G122673668, G1286236842, G1453181110, G1677143136, G1863003419, Track 4: Advanced CI Coordination Ecosystem: Monitoring and Measurement Services, G3562386289, G3598074284, G3666057378, G382641700, Track 1: ACCESS Resource Allocations Marketplace and Platform Services (RAMPS), G4010157413, G419881185, G42916606, G4501827968, G4566295880, ACO: An Open CI Ecosystem to Advance Scientific Discovery (OpenCI), G498139845, G5076365615, Track 3: COre National Ecosystem for CyberinfrasTructure (CONECT), G5367127336, G5464919783, G6049520747, G6652958823, Track 2: Customized Multi-tier Assistance, Training, and Computational Help (MATCH) for End User ACCESS to CI
OpenAlex ID: W7221545978