This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. Involved in autophagy in response to starvation. Upon interaction with VMP1 and activation, controls ER-isolation membrane contacts for autophagosome formation. Also modulates ER contacts with lipid droplets, mitochondria and endosomes. Involved in the regulation of the contraction/relaxation cycle. Acts as a regulator of TNFSF11-mediated Ca(2+) signaling pathways via its interaction with TMEM64 which is critical for the TNFSF11-induced CREB1 activation and mitochondrial ROS generation necessary for proper osteoclast generation. Association between TMEM64 and SERCA2 in the ER leads to cytosolic Ca(2+) spiking for activation of NFATC1 and production of mitochondrial ROS, thereby triggering Ca(2+) signaling cascades that promote osteoclast differentiation and activation. ATP + Ca(2+)(in) + H2O = ADP + Ca(2+)(out) + H(+) + phosphate Has different conformational states with differential Ca2+ affinity. The E1 conformational state (active form) shows high Ca(2+) affinity, while the E2 state exhibits low Ca(2+) affinity. Reversibly inhibited by phospholamban (PLN) at low calcium concentrations. Inhibited by sarcolipin (SLN) and myoregulin (MRLN). The inhibition is blocked by VMP1 (By similarity). Enhanced by DWORF; DWORF increases activity by displacing sarcolipin (SLN), phospholamban (PLN) and myoregulin (MRLN) (By similarity). Stabilizes SERCA2 in its E2 state (By similarity). Interacts with sarcolipin (SLN); the interaction inhibits ATP2A2 Ca(2+) affinity. Interacts with phospholamban (PLN); the interaction inhibits ATP2A2 Ca(2+) affinity (By similarity). Interacts with myoregulin (MRLN) (By similarity). Interacts with DWORF (By similarity). Interacts with HAX1 (By similarity). Interacts with S100A8 and S100A9 (By similarity). Interacts with SLC35G1 and STIM1. Interacts with TMEM203 (By similarity). Interacts with TMEM64 and PDIA3 (By similarity). Interacts with TMX2 (By similarity). Interacts with VMP1; VMP1 competes with PLN and SLN to prevent them from forming an inhibitory complex with ATP2A2. Interacts with ULK1 (By similarity). Interacts with S100A1 in a Ca(2+)-dependent manner (By similarity). Interacts with TUNAR (By similarity). Interacts with TRAM2 (via C-terminus). Isoform 1 is expressed in the heart. Ca(2+) and ATP binding cause major rearrangements of the cytoplasmic and transmembrane domains. According to the E1-E2 model, Ca(2+) binding to the cytosolic domain of the pump in the high-affinity E1 conformation is followed by the ATP-dependent phosphorylation of the active site Asp, giving rise to E1P. A conformational change of the phosphoenzyme gives rise to the low-affinity E2P state that exposes the Ca(2+) ions to the lumenal side and promotes Ca(2+) release. Dephosphorylation of the active site Asp mediates the subsequent return to the E1 conformation. PLN and SLN both have a single transmembrane helix; both occupy a similar binding site that is situated between the ATP2A2 transmembrane helices. Nitrated under oxidative stress. Nitration on the two tyrosine residues inhibits catalytic activity. Serotonylated on Gln residues by TGM2 in response to hypoxia, leading to its inactivation. Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IIA subfamily.