Interactions of the intrinsically disordered selenoprotein S with a small GTPase regulator

Abstract

Selenoproteins are a family of enzymes that employ the rare amino acid selenocysteine to catalyze chemical reactions. Among them, selenoprotein S stands out because the selenocysteine is positioned in an intrinsically disordered segment. The physiological function of this enzyme is unknown, although it was shown to take part in ER homeostasis by mediating protein degradation and may also have a role in vesicle trafficking, lipid metabolism, and management of oxidative stress. To elucidate its function in vesicle trafficking, we demonstrate that selenoprotein S binds the nucleotide exchange regulator of small GTPases, SmgGDS, a regulator of the Ras and Rho family members. Curiously, both selenoprotein S and SmgGDS are hijacked by non‐structural proteins of SARS‐CoV‐2, along with other proteins involved in maintaining ER homeostasis and regulation of the secretory pathway. To investigate this link, we have characterized the interactions between selenoprotein S and SmgGDS. We show that the interaction requires the hydrophobic segment of selenoprotein S, previously thought to be transmembrane. We describe biochemical assays to examine the putative role of selenoprotein S in modulating SmgGDS function and whether it accelerates the rate release of GTPases from SmgGDS.