Thus C-terminal tagging of progranulin should be avoided in order to preserve the interaction between progranulin and sortilin. Since the minimum requirement for sortilin binding is fairly degenerate, our study also raises the question about the specificity of the progranulin-sortilin interaction. Progranulin does not interact with other mammalian sortilin homologs, such as sorLA and sorCS1, suggesting that the specific organization of the sortilin beta-propeller region is required for this binding to occur. Sortilin is a multi-functional receptor with many identified ligands. Some of the ligands, such as cathepsin D also have C-terminal leucine residues. While it remains to be determined whether cathepsin D interacts with sortilin through its C-terminal leucine residue, there might be other unknown ligands for sortilin that bind through similar mechanisms. The C-terminal peptide of progranulin is the only binding site for sortilin in progranulin. The granulin motif does not bind to sortilin and possesses unique biological activities in proliferation, inflammation and wound healing. This indicates there exist other receptors that mediate the effects of progranulin or its cleaved products, granulin peptides. In this regard, a recent study demonstrated direction interactions between progranulin and tumor necrosis GSK J1 factor receptors. Our study also suggests that progranulin and pro-neurotrophins binds to sortilin through different sites. The pro-domain of nerve growth factor and brain derived neurotrophic factor binds to sortilin through a linear surface exposed sequence rather than interacting inside of the beta-propeller tunnel like neurotensin and progranulin. This binding motif is consistent with the published data that progranulin and pro-NGF can bind to sortilin simultaneously in a Surface Plasmon Resonance experiment. However, neurotensin Paederosidic-acid-methyl-ester blocks pro-neurotrophin induced neuronal cell death through sortilin although it binds to a different site. High levels of pro-NGF could also displace progranulin binding to sortilin. These data suggest that although progranulin and pro-neurotrophins interact with sortilin through different mechanisms, steric hindrance and possible effects on the assembly of the ligand-receptor signaling complex is still likely to happen with regards to progranulin affecting proneurotrophin binding to sortilin and signaling. Selenium is the only trace element found in proteins that is directly genetically encoded. The semi-metal is incorporated into selenoproteins in the form of selenocysteine by a cotranslational process using an intricate translation mechinery that redefines specific UGA codons to encode Sec. Selenium can also be severely toxic because of the high chemical reactivity of metabolites such as selenite and hydrogen selenide. Thus it is vital to both have adequate selenium intake and to develop means for tight control of the selenium metabolism.