SELENOPROTEIN P: An Extracellular Protein with Unique Physical Characteristics and a Role in Selenium Homeostasis

Abstract

Selenoprotein P is an abundant extracellular glycoprotein that is rich in selenocysteine. It has two domains with respect to selenium content. The N-terminal domain of the rat protein contains one selenocysteine residue in a UxxC redox motif. This domain also has a pH-sensitive heparin-binding site and two histidine-rich amino acid stretches. The smaller C-terminal domain contains nine selenocysteine and ten cysteine residues. Four isoforms of selenoprotein P are present in rat plasma. They share the same N terminus and amino acid sequence. One isoform is full length and the three others terminate at the positions of the second, third, and seventh selenocysteine residues. Selenoprotein P turns over rapidly in rat plasma with the consequence that approximately 25% of the amount of whole-body selenium passes through it each day. Evidence supports functions of the protein in selenium homeostasis and oxidant defense. Selenoprotein P knockout mice have very low selenium concentrations in the brain, the testis, and the fetus, with severe pathophysiological consequences in each tissue. In addition, those mice waste moderate amounts of selenium in the urine. Selenoprotein P binds to endothelial cells in the rat, and plasma levels of the protein correlate with prevention of diquat-induced lipid peroxidation and hepatic endothelial cell injury. The mechanisms of these apparent functions remain speculative and much work on the mechanism of selenoprotein P function lies ahead. Measurement of selenoprotein P in human plasma has shown that it is depressed by selenium deficiency and by cirrhosis. Selenium supplementation of selenium-deficient human subjects showed that glutathione peroxidase activity was optimized before selenoprotein P concentration was optimized, indicating that plasma selenoprotein P is the better index of human selenium nutritional status.

Selenium biochemistry and its role for human health

“…17 The concentration of SelP reflects mostly the short-term status of Se in the organism because it has a half-life in plasma of few hours (3-4 h in rat plasma). 18 This makes it a better marker than GPx3 for the assessment of the Se nutritional status. Nevertheless, once the basal Se requirement is reached, additional increase of the element does not lead to an increase in GPx3 or SelP concentration, therefore such Se biomarkers have limited validity.…”

“…As mentioned in Section 3.3, evidence supports functions of SelP in Se transport and homeostasis throughout the whole body. 18 SelP knockout mice present very low Se concentrations in brain, testis and foetus, with severe pathophysiological consequences in each tissue. 123 In addition, these mice excrete moderate amounts of Se in the urine.…”

“…18,127 In addition, SelP binds to endothelial cells in the rat, probably through its heparine-binding site. 18 …”

Polymorphisms in the selenoprotein S and 15-kDa selenoprotein genes are associated with altered susceptibility to colorectal cancer

“…Selenocysteine is incorporated into selenoproteins during their synthesis with a specific stem-loop structure in the 3 0 untranslated region (3 0 UTR) of the mRNAs required to recode a UGA codon from ''stop'' to selenocysteine [2]. These selenoproteins include the family of glutathione peroxidises [4], selenoprotein P (SePP) which has a Se transport role [5], selenoprotein S which is an endoplasmic reticulum protein involved in removing unfolded proteins and the 15-kDa selenoprotein which is also an endoplasmic reticulum protein involved in the unfolded protein response [11,18]. Because the selenoproteins have important roles in cell stress responses and redox control [2,4], it is possible that genetic variation due to single nucleotide polymorphisms (SNP) in the genes encoding the selenoproteins may influence susceptibility to cancer and Se requirements for optimal health.…”

Plasma Selenium Measurements in Subjects from Areas with Contrasting Gastric Cancer Risks in Colombia

“…Sepp1 distributes Se and controls cell redox status (45). Therefore, Sepp1 is a key factor in Se homeostasis and host oxidant defense.…”