Ca2ATPase

Ca2+-ATPases are membrane-bound enzymes that actively transport calcium ions (Ca2+) out of the cytosol against their electrochemical gradient, using energy from ATP hydrolysis. They are essential for maintaining low cytosolic Ca2+ concentration and for refilling calcium stores in organelles, which supports processes such as muscle relaxation, neurotransmitter release, and various signaling pathways.

The Ca2+-ATPase family includes three main subfamilies: SERCA (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase), PMCA (plasma membrane Ca2+-ATPase), and SPCA (secretory pathway Ca2+-ATPase). SERCA pumps are located in the sarcoplasmic reticulum and endoplasmic reticulum of muscle and other cells; PMCA pumps reside in the plasma membrane; SPCA enzymes transport Ca2+ into Golgi and other secretory organelles. Different isoforms (for example SERCA1–3, PMCA1–4, SPCA1–2) confer tissue-specific Ca2+ handling.

Mechanistically, Ca2+-ATPases belong to the P-type ATPase family. They alternate between E1 and E2 conformations. In the E1 state, Ca2+ binds to sites on the cytosolic side; ATP then drives phosphorylation of a conserved aspartate in the P-domain, triggering a conformational transition to E2 that releases Ca2+ into the lumen or extracellular space. Dephosphorylation returns the pump to E1. In SERCA, two Ca2+ ions are typically moved per ATP hydrolyzed; PMCA generally transfers one Ca2+ per ATP.

Structural features include about 10 transmembrane helices and three cytosolic domains: actuator (A), phosphorylation (P), and nucleotide-binding (N). The P-domain contains the key aspartate phosphorylation site, and characteristic motifs coordinate energy transduction and ion binding.

Regulation and disease: activity is modulated by accessory proteins such as phospholamban in muscle; mutations in ATP2A2 (SERCA2) cause Darier disease, while mutations in ATP2C1 (SPCA1) cause Hailey–Hailey disease, reflecting the importance of Ca2+-ATPases in calcium homeostasis.