Figure 1. Synthesis of secretory and nuclear clusterin proteins. (a) Synthesis of secretory clusterin (sCLU) protein forms is depicted. Full length clusterin (CLU) mRNA is translated with a leader polypeptide that targets the protein to endoplasmic reticulum (ER). The ER polypeptide is cleaved and a 60 kDa pre-secretory clusterin (psCLU) protein is produced. As the protein is transported to the Golgi complex, it is cleaved into and polypeptides, which are heavily glycosylated and form a heterodimeric complex via five disulfide bonds. Ultimately, an 80 kDa protein is excreted from the cell. (b) Intracellular CLU protein is produced from a truncated, alternatively spliced nuclear clusterin (nCLU) mRNA, which lacks the ER-targeting domain [14]. Translation of the nCLU mRNA results in 49 kDa pre-nuclear clusterin (pnCLU) protein. This 49 kDa pnCLU is dormant in the cytoplasm, presumably by hiding the nuclear localisation site (NLS) within the C-terminal portion of the protein through homodimerisation or self-folding of the protein; pnCLU contains two coiled-coil domains that interact and cause dormancy. After significant stress (>1 Gy), pnCLU is "activated" and altered post-translationally, forming an 55 kDa cell death protein. Expression of the C-terminus of this nCLU protein was sufficient to cause cell death [14].