Figure 1

SERCA1a reaction cycle. Scheme shows the main steps for substrates binding and dissociation. At physiological pH, two cytoplasmic calcium ions bind to the “E1” high-affinity states. Binding of one Mg.ATP triggers calcium occlusion and allows autophosphorylation on the catalytic aspartate localized in P-domain (“Ca₂.E1 ~ P” occluded state). The energy transferred from the nucleotide to the protein allows large conformational changes necessary for transport sites reorientation towards the lumen and then, for releasing of calcium ions against a concentration gradient. Protonation of the transport sites and autodephosphorylation of the Ca²⁺-free “E2-P” state enable cycling of the enzyme. Note that ATP can bind to most of these intermediates to act as a positive modulator and to accelerate transitions¹. Orthovanadate (VO₄) can act as an inhibitor after binding to the E2 ground state.