Calcium-Driven Activation of Gelsolin: Mechanism and the Active-State Ensemble
- 1Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Via Alfonso Corti 12, 20133 Milano, Italy
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.
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BibTeX
@misc{stegani2026calciumdriven,
title = {{Calcium-Driven Activation of Gelsolin: Mechanism and the Active-State Ensemble}},
author = {B. Stegani and L. Girois and F. Ballabio and T. Giorgino and R. Capelli and G. Gerbaud and M. Bollati and M. Milani and A. Bonucci and C. Camilloni and M. de Rosa},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.16.759396},
url = {https://www.biorxiv.org/content/10.64898/2026.10.16.759396v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Calcium-Driven Activation of Gelsolin: Mechanism and the Active-State Ensemble
AU - B. Stegani
AU - L. Girois
AU - F. Ballabio
AU - T. Giorgino
AU - R. Capelli
AU - G. Gerbaud
AU - M. Bollati
AU - M. Milani
AU - A. Bonucci
AU - C. Camilloni
AU - M. de Rosa
PY - 2026
DA - 2026/10/16
PB - bioRxiv
DO - 10.64898/2026.10.16.759396
UR - https://www.biorxiv.org/content/10.64898/2026.10.16.759396v1
AB - 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.
ER -