3.A.3.2.5
The Golgi Ca²⁺, Mn²⁺-ATPase, human SPCA1 or SPCA1a (secretory-pathway Ca²⁺-ATPases (SPCAs)), ATP2C1 or Hussy-28 (efflux) (the Hailey-Hailey disease protein) is involved in responses to Golgi stress, apoptosis and mid-gestational death (Okunade et al., 2007). SPCA1 transports Mn²⁺ from the cytosol into the Golgi lumen. Increasing Golgi Mn²⁺ transport increased cell viability upon Mn²⁺ exposure, supporting a role in the management of Mn²⁺-induced neurotoxicity (Mukhopadhyay and Linstedt, 2011). SPCA1 governs the stability of TMEM165 (TC# 2.A.106.2.2) in Hailey-Hailey disease (Roy et al. 2020). Loss of ATP2C1 leads to impaired Notch1 signalling; ATP2C1-loss could promote a mechanism by which NOTCH1 is endocytosed and degraded (Zonfrilli et al. 2023).  Six cryo-EM structures of hSPCA1 in a series of intermediate states have revealed its near-complete conformational cycle (Wu et al. 2023). With the aid of molecular dynamics simulations, these structures offer a clear structural basis for Ca²⁺ entry and release in hSPCA1. hSPCA1 undergoes unique conformational changes during ATP binding and phosphorylation compared to other well-studied P-type II ATPases. In addition, a conformational distortion of the Ca²⁺-binding site induced by the separation of transmembrane helices 4L and 6 unveiling a distinct Ca²⁺ release mechanism. A structure of the long-sought CaE2P state of P-type IIA ATPases provided insight into the Ca²⁺ transport cycle (Wu et al. 2023). Structures of human SPCA1a in the ATP and Ca²⁺/Mn²⁺-bound (E1-ATP) state and the metal-free phosphorylated (E2P) state at 3.1- to 3.3-Å resolutions (Chen et al. 2023). The structures revealed that Ca²⁺ and Mn²⁺ share the same metal ion-binding pocket with similar but notably different coordination geometries in the transmembrane domain, corresponding to the second Ca²⁺-binding site in sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA).