{
  "abstract": "Gelsolin is a master regulator of the actin cytoskeleton whose activity is controlled by large Ca2+ dependent conformational transitions of its 6 domains (G1-G6). Despite decades of biochemical and cellular studies, the structural basis of activation of the full-length protein remains poorly understood because active gelsolin is highly dynamic and has largely escaped structural characterization. Here, we combine small-angle X-ray scattering, DEER-EPR spectroscopy, and structure-based molecular dynamics simulations to investigate the transition from the compact inactive state to the actin-binding active form. This integrative approach reveals that activation proceeds through a sequential and domain-dependent mechanism, where different regions of the protein respond to Ca2+ with distinct kinetics and conformational trajectories. Rather than converging toward a single active structure, activated gelsolin populates a heterogeneous ensemble of plastic conformations characterized by asymmetric domain arrangements and extensive structural variability. The two major domain triplets (G1-G3 and G4-G6) display markedly different dynamic behaviors, while actin-binding surfaces are exposed according to a defined hierarchy and remain differentially accessible within the active ensemble, suggesting specialized functional roles for different domains during filament engagement. Together, these findings provide a time- and domain-resolved view of gelsolin activation, establish a structural framework for interpreting its diverse biological functions, and offer new opportunities for targeting gelsolin-associated diseases.",
  "abstract_shown": true,
  "affiliations": [
    "Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Via Alfonso Corti 12, 20133 Milano, Italy"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "B. Stegani"
    },
    {
      "name": "L. Girois"
    },
    {
      "name": "F. Ballabio"
    },
    {
      "name": "T. Giorgino"
    },
    {
      "name": "R. Capelli"
    },
    {
      "name": "G. Gerbaud"
    },
    {
      "name": "M. Bollati"
    },
    {
      "name": "M. Milani"
    },
    {
      "name": "A. Bonucci"
    },
    {
      "name": "C. Camilloni"
    },
    {
      "affs": [
        0
      ],
      "name": "M. de Rosa"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/egh5pnwc36w98.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.16.759396",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.16.759396v1.full",
  "id": "egh5pnwc36w98",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.16.759396v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biophysics"
    ],
    [
      "openalex",
      "1312|Protein Structure and Dynamics"
    ]
  ],
  "openalex": "W7223201236",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.16.759396v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-16",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/egh5pnwc36w98.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:10Z",
      "native_id": "10.64898/2026.10.16.759396",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.16.759396v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biophysics",
      "subfield": "biophysics"
    }
  ],
  "title": "Calcium-Driven Activation of Gelsolin: Mechanism and the Active-State Ensemble",
  "title_text": "Calcium-Driven Activation of Gelsolin: Mechanism and the Active-State Ensemble",
  "type": "preprint",
  "updated_at": "2026-10-30T12:29:10Z",
  "url": "https://research.draconitic.com/paper/egh5pnwc36w98",
  "venue": "bioRxiv",
  "versions": []
}