{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pharmacology and Computational Medicine Program, Bioinformatics and Computational Biology Program, University of North Carolina - Chapel Hill"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "name": "K. Joshi"
    },
    {
      "name": "B. S. Magenheimer"
    },
    {
      "name": "A. Haldane"
    },
    {
      "name": "Y. Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Y. Miao"
    },
    {
      "name": "R. L. Maser"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/44s0jjgkp0fng.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.10.758211",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.10.758211v1.full",
  "id": "44s0jjgkp0fng",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.10.758211v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "bioinformatics"
    ],
    [
      "openalex",
      "1312|Receptor Mechanisms and Signaling"
    ]
  ],
  "openalex": "W7221545978",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.10.758211v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-10",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/44s0jjgkp0fng.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:27:20Z",
      "native_id": "10.64898/2026.10.10.758211",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.10.758211v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioinformatics",
      "subfield": "bioinformatics"
    }
  ],
  "title": "Activation of Disease-Associated Polycystin-1 Mutants by Binding of Stalk-derived Agonist Peptides",
  "title_text": "Activation of Disease-Associated Polycystin-1 Mutants by Binding of Stalk-derived Agonist Peptides",
  "type": "preprint",
  "updated_at": "2026-10-30T12:27:20Z",
  "url": "https://research.draconitic.com/paper/44s0jjgkp0fng",
  "venue": "bioRxiv",
  "versions": []
}