Figure 10. Summary of CLU mRNA transcripts and translated protein isoforms in the brain.

Three previously described and one newly hypothesized CLU mRNA transcript result in the production of five distinct protein isoforms, including one mature isoform with associated intermediates and three intracellular isoforms. The mCLU pre-protein is generated via translation of Exon-1B-containing mRNA (astrocytes and neurons; middle panel) and Exon-1A-containing mRNA (astrocytes only; upper panel). Once the mCLU pre-protein is translated, the 21-amino-acid ER-targeting sequence (majority of Exon 2) is cleaved and the resultant 427-amino-acid protein (CLU_49 kDa) is glycosylated, first by high mannose glycans (CLU_60 kDa) and then by complex glycans, followed by proteolytic cleavage to form mCLUβ (CLU_34–36 kDa) and mCLUα (CLU_36–39 kDa). Heterodimerization by five disulfide bonds results in the formation of mature CLU (mCLU; CLU_70–75 kDa), which can then be secreted into the extracellular space. In addition, on the basis of our data, we hypothesize that the Exon -C-containing mRNA transcript results in the production of the intracellular CLU protein isoform, icCLU_53 kDa, which is then post-translationally modified to form nCLU_68 kDa. The spliced transcript containing Exons 3–9 results in the production of mitoCLU_45 kDa, which is present in both human and rodent brain mitochondria and is translated from a non-canonical CUG start site in rodents.