ATP2A2

This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of the skeletal muscle. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol into the sarcoplasmic reticulum lumen, and is involved in regulation of the contraction/relaxation cycle. Mutations in this gene cause Darier-White disease, also known as keratosis follicularis, an autosomal dominant skin disorder characterized by loss of adhesion between epidermal cells and abnormal keratinization. Other types of mutations in this gene have been associated with various forms of muscular dystrophies. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2019]
Diseases associated with ATP2A2 include Darier-White Disease and Acrokeratosis Verruciformis. Among its related pathways are Cardiac conduction and Pre-NOTCH Expression and Processing. Gene Ontology (GO) annotations related to this gene include calcium ion binding and enzyme binding. An important paralog of this gene is ATP2A1.
This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen (PubMed:12542527, 16402920).
Involved in autophagy in response to starvation.
Upon interaction with VMP1 and activation, controls ER-isolation membrane contacts for autophagosome formation (PubMed:28890335).
Also modulates ER contacts with lipid droplets, mitochondria and endosomes (PubMed:28890335).
In coordination with FLVCR2 mediates heme-stimulated switching from mitochondrial ATP synthesis to thermogenesis (By similarity).
[Isoform 2]: 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.
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 (PubMed:28890335).
Enhanced by DWORF; DWORF increases activity by displacing sarcolipin (SLN), phospholamban (PLN) and myoregulin (MRLN) (By similarity).
Stabilizes SERCA2 in its E2 state (PubMed:28890335).
ATPase,Ca++ transporting,expressed in the sarcoplasmic reticullum of the heart (SERCA2A) rate determining factor of Ca2+ reuptake into the SR,regulated by phospholamban,also expressed in the heart,slow-twitch muscle,highly expressed in keratinocytes,including two isoforms,a (D12S2026),b (D12S1965). Ca2+ pump,playing a pivotal role in intracellular Ca2+ signaling
Endoplasmic reticulum membrane; Multi-pass membrane protein {ECO:0000250 UniProtKB:O55143 | ECO:0000255}5
Sarcoplasmic reticulum membrane; Multi-pass membrane protein {ECO:0000269 PubMed:12804600 | ECO:0000255}5
Note: Colocalizes with FLVCR2 at the mitochondrial-ER contact junction {ECO:0000250 UniProtKB:O55143}
Quaternary structure:
Interacts with sarcolipin (SLN); the interaction inhibits ATP2A2 Ca(2+) affinity (PubMed:28890335).
Interacts with phospholamban (PLN); the interaction inhibits ATP2A2 Ca(2+) affinity (PubMed:28890335).
Interacts with myoregulin (MRLN) (By similarity).
Interacts with DWORF (By similarity).
Interacts with HAX1 (PubMed:18971376).
Interacts with S100A8 and S100A9 (By similarity).
Interacts with SLC35G1 and STIM1 (PubMed:22084111).
Interacts with TMEM203 (PubMed:25996873).
Interacts with TMEM64 and PDIA3 (By similarity).
Interacts with TMX1 (PubMed:27502484).
Interacts with TMX2 (PubMed:31735293).
Interacts with VMP1; VMP1 competes with PLN and SLN to prevent them from forming an inhibitory complex with ATP2A2 (PubMed:28890335).
Interacts with ULK1 (PubMed:28890335).
Interacts with S100A1 in a Ca(2+)-dependent manner (PubMed:12804600).
Interacts with TUNAR (By similarity).
Interacts with FLVCR2; this interaction occurs in the absence of heme and promotes ATP2A2 proteasomal degradation; this complex is dissociated upon heme binding (By similarity).
Interacts with FNIP1 (By similarity).
[Isoform 1]: Interacts with TRAM2 (via C-terminus).