3.A.3.2.43
SERCA1 of 1001 aas.  Several 3-D structures are known (e.g., 3W5B). One has an ATP analogue, a Mg²⁺ and two Ca²⁺ ions in the respective binding sites (Toyoshima and Mizutani 2004). In this state, the ATP reorganizes the three cytoplasmic domains (A, N and P), which are widely separated without nucleotide, by directly bridging the N and P domains. The structure of the P-domain itself is altered by the binding of the ATP analogue and Mg²⁺. As a result, the A-domain is tilted so that one of the TMSs moves to lock the cytoplasmic gate of the transmembrane Ca²⁺-binding sites. This appears to be the mechanism for occluding the bound Ca²⁺ ions, before releasing them into the lumen of the sarcoplasmic reticulum (Toyoshima and Mizutani 2004). Molecular dynamics simulations provided evidence for the role of the Mg²⁺ and K⁺ bound states in the transport mechanism (Espinoza-Fonseca et al. 2014).  Animal SERCAs are inhibited by three short single 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).  Norimatsu et al. 2017 have resolved the first layer of phospholipids surrounding the transmembrane helices. Phospholipids follow the movements of associated residues, causing local distortions and changes in thickness of the bilayer. The entire protein tilts during the reaction cycle, governed primarily by a belt of Trp residues, to minimize energy costs accompanying the large perpendicular movements of the transmembrane helices. A class of Arg residues extend their side chains through the cytoplasm to exploit phospholipids as anchors for conformational switching (Norimatsu et al. 2017). The human ortholog (O14983) is 96% identical to this rabbit enzyme.  These enzymes are inhibited by the fungal mycotoxins, cyclopiazonic acid and thapsigargin (Darby et al. 2016; Houdou et al. 2019). The human ortholog is 97% identical and is of the same length. The SERCA residue Glu340 mediates interdomain communication that guides Ca²⁺ transport (Geurts et al. 2020). The SERCA Ca²⁺-ATPase may serve as a calcium-sensitive membrane-endoskeleton sensor in the sarcoplasmic reticulum (Nakamura et al. 2021). The C-terminal proton release pathway is a functional element of SERCA which provides a mechanistic model for its operation in the catalytic cycle of the pump (Espinoza-Fonseca 2021).