Unveiling the intricate role of S100A1 in regulating RyR1 activity: A commentary on "Structural insights into the regulation of RyR1 by S100A1"

Abstract

S100A1, a calcium-binding protein, plays a crucial role in regulating Ca²⁺ signaling pathways in skeletal and cardiac myocytes via interactions with the ryanodine receptor (RyR) to affect Ca²⁺ release and contractile performance. Biophysical studies strongly suggest that S100A1 interacts with RyRs but have been inconclusive about both the nature of this interaction and its competition with another important calcium-binding protein, calmodulin (CaM). Thus, high-resolution cryo-EM studies of RyRs in the presence of S100A1, with or without additional CaM, were needed. The elegant work by Weninger et al. demonstrates the interaction between S100A1 and RyR1 through various experiments and confirms that S100A1 activates RyR1 at sub-micromolar Ca²⁺ concentrations, increasing the open probability of RyR1 channels.

Keywords: Ca(V)1.1; CaM; Calcium release; Cryo-EM; Muscle contraction; RyR1; S100A1; modulation.

Fig. 1.

Hypothesized effects of S100A1 and CaM on RyR1-mediated calcium release in physiological context. A) During a single action potential (AP) twitch, free calcium levels remain low enough that CaM remains in its apo form (dark blue) and are high enough that a proportion of S100A1 molecules take their calcium-bound form (orange). When bound to the RyR (gray) these proteins have weakly activating and activating effects, respectively. (RyR1:apo-CaM, PDB 6 × 32; RyR1:Ca-S100A1, PDB 8VK4) B) During early tetanus (orange shaded box), calcium levels fully activate S100A1 without activating CaM, allowing full activation of RyR1 and maximal calcium release from the SR. C) When calcium levels climb to high levels in late tetanus (light blue shaded box), calcium-bound CaM (light blue) binds RyR1 and blocks S100A1 access to the site. This inhibits RyR1 and decreases calcium release from the SR. (RyR1:Ca-CaM, PDB 7TZC). Scale of both traces: 1 uM [Ca²⁺] (y-axis), 50 ms (x-axis). Created with BioRender; protein structures captured from.