Fig. 2

Schematic diagram of SLC10A7 protein and function. (A) Distribution of 12 reported variants. Nonsense variant of our case was labeled in red. (B,C) Predicted 3D structure of SLC10A7 protein. It was predicted using AphlaFold2 (https://www.alphafold.ebi.ac.uk/), and depicted using PyMOL (https://www.pymol.org). (B) Lateral side of protein. (C) Top side of protein depicted from luminal side. (D) SLC10A7 as a negative regulator of Ca²⁺ hemostasis by inhibiting Orai1 and SERCA. After GPCR activation, PLC hydrolyses PIP2 to IP3. The latter binds to IP3R and leads to depletion of ER Ca²⁺ store. ER Ca²⁺ sensor STIM1 oligomerizes and recruits Orai1 to ER-PM junction and stimulates Orai1-operated Ca²⁺ influx. Then, ER Ca²⁺ store is refilled by SERCA pumping cytoplasmic Ca²⁺ into ER. SLC10A7 could inhibit the STIM1, Orai1 and SERCA to negatively regulate Ca²⁺ uptake, thus SSASKS-causing SLC10A7 mutations increase Ca²⁺ influx. Abbreviations, TM, trans-membrane; N-term, N termination of protein; C-term, C termination of protein; GPCR, G protein-coupled receptors; PLC, phospholipase C; PIP2, phosphatidylinositol (4, 5) bisphosphate (PI (4, 5) P2); IP3, inositol triphosphate; IP3R, IP3 receptor; SERCA2, sarcoplasmic/endoplasmic reticulum calcium ATPase 2