{
  "abstract": "HER2, an ERBB2-encoded receptor tyrosine kinase, regulates cell growth and survival. HER2 overexpression or ERBB2 amplification can promote tumor growth and is used to identify cancers that may benefit from HER2-targeted therapies. However, the functional consequences of sequence variants are difficult to predict when they occur outside known functional sites. Cysteine-introducing variants pose a challenge because a new cysteine can either form an abnormal bond directly or disrupt an existing disulfide and change which interactions are possible. HER2 W452C variant provides a case study of this problem because it introduces a cysteine outside the canonical dimerization interface but near a native extracellular disulfide. We used structural modeling, molecular dynamics, protein-protein docking, and cell-based analysis to test how W452C could alter receptor organization. Direct C452-C452 pairing between HER2 receptors was consistently difficult to accommodate without severe receptor overlap. We therefore examined a conditional state in which the native disulfide was reorganized, leaving another cysteine available for intermolecular interaction. This state increased ectodomain flexibility and accommodated alternative cysteine-mediated contacts. Explicit-bond refinement showed that selected C452-C504 arrangements remained structurally compatible after covalent disulfide formation. In cells, W452C increased a DTT-sensitive high-molecular-weight HER2-containing species, supporting altered disulfide-dependent association. Together, these findings support a mechanism in which an introduced cysteine alters receptor organization by reorganizing the local disulfide network rather than simply forming a new bond itself. More broadly, they illustrate how structural analysis can reveal molecular consequences of genetic variants that are not apparent from sequence position alone and thereby inform precision-medicine variant interpretation.",
  "abstract_shown": true,
  "affiliations": [
    "Center for Precision Medicine and Data Sciences, University of California, Davis, School of Medicine, Sacramento, CA, USA.",
    "Department of Physiology and Membrane Biology, University of California, Davis, School of Medicine, Davis, CA, USA.",
    "Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Sacramento, CA, USA.",
    "Department of Pharmacology, University of California, Davis, School of Medicine, Davis, CA, USA."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Khoa Ngo",
      "orcid": "0000-0002-7454-2924"
    },
    {
      "affs": [
        2
      ],
      "name": "Matthew Saldaña"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Hajar Amini"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Kermit L Carraway"
    },
    {
      "affs": [
        0,
        1,
        3
      ],
      "name": "Colleen E Clancy",
      "orcid": "0000-0001-6849-4885"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9chdeq2x3yczg.bib",
  "cited_by": 0,
  "doi": "10.1016/j.premed.2026.100064",
  "fulltext_url": "https://europepmc.org/articles/PMC13712401",
  "id": "9chdeq2x3yczg",
  "issns": [
    "3050-6328"
  ],
  "landing_url": "https://europepmc.org/article/MED/42948421",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2730|HER2/EGFR in Cancer Research"
    ]
  ],
  "openalex": "W7220832583",
  "pdf_url": "https://europepmc.org/articles/PMC13712401?pdf=render",
  "pmcid": "PMC13712401",
  "pmid": "42948421",
  "published": "2026-10-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/9chdeq2x3yczg.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T00:20:34Z",
      "native_id": "MED:42948421",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42948421"
    },
    {
      "first_seen": "2026-11-01T12:23:42Z",
      "native_id": "PMC13712401",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.premed.2026.100064"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|HER2/EGFR in Cancer Research",
      "subfield": "oncology"
    }
  ],
  "title": "Structural modeling predicts altered disulfide connectivity in HER2 W452C.",
  "title_text": "Structural modeling predicts altered disulfide connectivity in HER2 W452C.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-02T12:20:55Z",
  "url": "https://research.draconitic.com/paper/9chdeq2x3yczg",
  "venue": "Journal of precision medicine (Amsterdam, Netherlands)",
  "versions": []
}