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bioRxiv · 10.64898/2026.04.04.716468

Cardiac Calsequestrin is a Physiological Dimer that Polymerizes through a Ca2+-Triggered Cooperative Switch

Marabelli, C.·Santiago, D. J.·Pirana, E.·Di Antonio, C.·Canciani, A.·Bolognesi, M.·Forneris, F.·Priori, S. G.
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Abstract

Cardiac Calsequestrin (CASQ2) polymerizes within the junctional sarcoplasmic reticulum to buffer Ca{superscript 2} and regulate ryanodine receptor 2 (RyR2) gating, yet the molecular mechanism governing this process remains poorly understood. Using an integrated set of complementary approaches spanning single-particle biophysics, bulk solution measurements, and polymer chemistry, we demonstrate that CASQ2 is an intrinsic dimer at nanomolar concentrations and under physiological ionic conditions, independently of Ca{superscript 2}. In addition, Ca{superscript 2}-dependent polymerization operates as a highly cooperative switch between a stable oligomeric phase and a high-order polymeric state. Physiological amounts of K ions modulate this switch through a biphasic electrostatic mechanism, supporting polymerization at low concentrations and inhibiting it beyond charge neutralization ([~]194 mM). These findings redefine CASQ2 as an intrinsic dimer with polymerization-switch properties, and provide a mechanistic framework for understanding how catecholaminergic polymorphic ventricular tachycardia type 2 mutations, distributed evenly across the CASQ2 surface, cause disease through two distinct pathological trajectories.

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Marabelli, C., Santiago, D. J., Pirana, E., Di Antonio, C., Canciani, A., Bolognesi, M., Forneris, F., Priori, S. G.. 2026-04-07. Cardiac Calsequestrin is a Physiological Dimer that Polymerizes through a Ca2+-Triggered Cooperative Switch. https://doi.org/10.64898/2026.04.04.716468

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