Abstract Fri092: Selenoprotein S – New binding partner and potential regulator of Sarcoendoplasmic Reticulum Calcium ATPase pump

Sarcoendoplasmic Reticulum Calcium ATPase (SERCA) regulates cellular calcium homeostasis by transporting Ca2+ from the cytosol back to the sarcoplasmic reticulum (SR) after muscle contraction. Its dysfunction is linked to heart failure. A class of small proteins, regulins, modulates SERCA activity and is considered a therapeutic target for heart disease. Selenoprotein S (selenos) is an ER-residing transmembrane protein with selenocysteine at its C-terminus. It plays a role in ER stress and oxidative stress responses. Selenos has been implicated in calcium flux regulation in some cell types, and its deletion in mice impairs fast-twitch muscle contraction. Additionally, single nucleotide polymorphisms within proximity of SELENOS gene are associated with cardiovascular diseases, prompting further investigation into its role in Ca2+ homeostasis. We first observed a connection between selenos and SERCA2 through a proteomics study in HEK293 cells, where SERCA2 was enriched among selenos-binding partners. Sequence analysis revealed that selenos shares a SERCA recognition motif with known regulins like DWORF and myoregulin and contains a leucine-zipper-like hydrophobic region similar to other regulins such as sarcolipin, phospholamban, and endoregulin. To confirm this interaction, we performed co-immunoprecipitation (co-IP) assays, demonstrating reciprocal binding between selenos and SERCA2. Since selenos is an oxidoreductase, it may influence SERCA function.