3.A.3.2.7
The sarco/endoplasmic reticulum Ca²⁺ -ATPase, SERCA2b or ATP2A2, is encoded by the ATP2A2 gene.  Mutatioins give rise to Darier''s disease; the spectrum of mutations have been related to patients' phenotypes (Ahn et al., 2003; Godic et al. 2010).  SERCA1 functions as a heat generator in mitochondria of brown adipose tissue (de Meis et al., 2006). It normally functions as a Ca²⁺:H⁺ antiporter (Karjalainen et al., 2007). Capsaicin converts SERCA to a Ca²⁺ non-transporting ATPase that generates heat, and is thus a natural drug that augments uncoupled SERCA, resulting in thermogenesis (Mahmmoud, 2008b). Oligomeric interactions of the N-terminus of sarcolipin with the Ca-ATPase have been documented (Autry et al., 2011), and these interactions also uncouple ATP hydrolysis from Ca²⁺ transport (Sahoo et al. 2015) resulting in thermogenesis.  TMS 11, absent in SERCA1a and SERCA2a, functions in regulation (Gorski et al. 2012). The bovine SERCA has also been crystallized (2.9 Å resolution; Sacchetto et al., 2012).  These enzymes are regulated differentially by phospholamban (PLN; 1.A.50.1.1) and sarcolipin (SLN; 1.A.50.2.1) as noted above (Gorski et al. 2013).  SERCA2 is regulated by TMEM64 (9.B.27.5.1), a 380 aa 6 TMS membrane protein of the DedA family (TC# 9.B.27) which regulates Ca²⁺ oscillations by direct interaction with CIRCA2, modulating its activity and influencing osteoblast differentiation (Kim et al. 2013).  Animal SERCAs are inhibited by three short single (C-terminal) TMS membrane proteins, phospholamban (TC# 1.A.50.1), sarcolipin (1.A.50.2) and myoregulin (1.A.50.3), and the inhibitory actions of these peptides on SERCA are counteracted by a peptide called DWORF (Dwarf ORF) (Nelson et al. 2016; Anderson et al. 2015). Small ankyrin 1 (sAnk1; TC#8.A.28.1.2) and sarcolipin (TC# 1.A.50.2.1) interact in their transmembrane domains to regulate SERCA (Desmond et al. 2017). Reduced SERCA function preferentially affects Wnt signaling by retaining E-cadherin in the endoplasmic reticulum and promotes apoptosis (Suisse and Treisman 2019). There is strong coupling between the chronological order of deprotonation, the entry of water molecules into the TM region, and the opening of the cytoplasmic gate. Deprotonation of E309 and E771 is sequential with E309 being the first to lose the proton. Deprotonation promotes the opening of the cytoplasmic gate but leads to a productive gating transition only if it occurs after the transmembrane domain has reached an intermediate conformation (Rui et al. 2018). Coordination at cation binding sites I and II is optimized for Ca²⁺ and to a lesser extent for Mg²⁺ and K⁺ (Sun et al. 2019). Methyglyoxal reacts with and inhibits SERCA (Zizkova et al. 2018). The phospholamban pentamer alters the function of SERCA (Glaves et al. 2019). TMS11 followed by the luminal tail is inhibitory. Inoue et al. 2019 determined the crystal structures of SERCA2b and its C-terminal splicing variant SERCA2a, both in the E1-2Ca²⁺-adenylylmethylenediphosphonate (AMPPCP) state. TMS11 is located adjacent to TMS10 and interacts weakly with a part of the L8/9 loop as well as the N-terminal end of TMS10, thereby inhibiting the SERCA2b catalytic cycle (Inoue et al. 2019). Accordingly, mutational disruption of the interactions between TMS11 and its neighboring residues caused SERCA2b to display SERCA2a-like ATPase activity. The authors proposed that TMS11 serves as a key modulator of SERCA2b activity by fine-tuning the intramolecular interactions with other transmembrane regions. Kabashima et al. 2020 revealed what ATP binding does to the Ca²⁺ pump and how nonproductive phosphoryl transfer is prevented in the absence of Ca²⁺. They reported that the A-domain takes an E1 position, and the N-domain occupies exactly the same position as that in the E1.ATP.2Ca²⁺ state relative to the P-domain. As a result, ATP is properly delivered to the phosphorylation site. Yet phosphoryl transfer never takes place without filling the two transmembrane Ca²⁺-binding sites. This explains what ATP binding does to SERCA, and how nonproductive phosphorylation is prevented in E2 (Kabashima et al. 2020). Nonannular lipid binding is not necessary for the stability of the E2 state but may become functionally significant during the E2-to-E1 transition (Espinoza-Fonseca 2019). Structural changes induced by the binding of rutin arachidonate to SERCA1a may shift proton balance near the titrable residues Glu771 and Glu309 into neutral species, hence preventing the binding of calcium ions to the transmembrane binding sites and thus affecting calcium homeostasis (Rodríguez and Májeková 2020). SERCA2a is a key protein in the Ca²⁺ cycle during heart failure (Zhihao et al. 2020). Covalent conjugates of fullerene derivatives with xanthene dyes inhibit SERCA (Tatyanenko et al. 2020). Autophosphorylation of the pump with two bound Ca²⁺ ions triggers a large conformational change that opens a gate on the luminal side of the membrane allowing the release of the ions. In response to phosphorylation, the cytoplasmic domains are partially reconfigured into an intermediate state on the path toward the E2 state with a closed luminal gate (Thirman et al. 2021). In preB cells, loss of SERCA2 leads to reduced V(D)J recombination kinetics due to diminished RAG-mediated DNA cleavage (Chen et al. 2021). A series of structural changes may accompany the ordered dissociation of ADP, the A-domain rotation, and the rearrangement of the transmembrane (TM) helices. The luminal gate then opens to release Ca²⁺ toward the SR lumen. Intermediate structures on the pathway are stabilized by transient sidechain interactions between the A- and P-domains. Lipid molecules between TM helices play a key role in the stabilization (Kobayashi et al. 2021). Structural bases for the conformational and functional regulation of human SERCA2b have been reported (Zhang and Inaba 2022). DWARF interacts with SERCA and phospholamban (PLB), counteracting the inhibitory effect of PLB on SERCA (Rustad et al. 2023). p300-mediated acetylation of SERCA2a is a critical post-translational modification that decreases the pump's function and contributes to cardiac impairment in heart failure (Gorski et al. 2023). Therapeutic approaches targeting SERCA2 and associated proteasomes might protect against Cd²⁺-induced cytotoxicity and renal injury (Li et al. 2023). SERCA2 phosphorylation at serine 663 is a key regulator of Ca²⁺ homeostasis in heart diseases (Gonnot et al. 2023).  The E protein of SARS-CoV-2 perturbes Ca²⁺ homeostasis. It is structurally similar to regulins such as phospholamban, that regulate the sarco/endoplasmic reticulum calcium ATPases (SERCA). The SARS-CoV-2 E protein affects SERCA as an exoregulin and forms oligomers with regulins, and thus alters the monomer/multimer regulin ratio thereby influencing their interactions with SERCAs. A direct interaction between E protein and SERCA2b results in a decrease in SERCA-mediated ER Ca²⁺ reload (Berta et al. 2024). Alarin regulates RyR2 and SERCA2 to improve cardiac function in heart failure with preserved ejection fraction (Li et al. 2024).