CLU (clusterin)

	A) Clusterin gene genomic location at chromosome 8p21-p12 (minus strand) and annotated transcripts. B) Exons are numbered and presented by boxes. Shaded areas represent untranslated regions (UTR). Endoplastic reticulum (ER)-targeting signal in exon 2 and nuclear localization signal (NLS) in exon 3 are marked. Three in-frame translation start sites in exons 1, 2 and 3 are marked (ATG).
Description	Clusterin gene is 17876 bp long and contains 10 exons in total. First two exons are alternative (designated 1 and 1') used by two different transcript isoforms. Other exons (2-9) are shared with both isoforms. CLU gene resides in minus strand and is transcribed in reverse orientation (from centromere to p-telomere).
Transcription	Clusterin gene is transcribed into 2 mRNA isoforms (NM-001831, 2859 bp; and NM-203339, 2979 bp). They result from the use of alternative first exons (1 and 1') and shared exons 2 to 9.

	Clusterin transcripts contain 3 different translation start sites (ATG), all in-frame. The best characterized protein isoform is produced from transcript isoform 2, where translation starts at the second ATG present in exon 2, right before ER-targeting signal. This protein (NP-976084) consists of 449 amino acids. The mechanism by which the protein products are translated from isoform 1 is not as well understood. There is evidence suggesting that two nuclear protein isoforms can be produced from this transcript isoform, one in which translation starts at ATG in exon 3 (417 aa), and another with translation starting from ATG in exon 1 (459 aa).
Description	Secreted clusterin is produced from the transcript isoform 2. The initial protein precursor, presecretory psCLU (~60 kDa), becomes heavily glycosylated and cleaved in the ER, and the resulting alpha and beta peptide chains are held together by 5 disulfide bonds in the mature secreted heterodimer protein form, sCLU (~75-80 kDa). Also the nuclear clusterin is first translated as a non-glycosylated protein precursor, pnCLU (~49 kDa), that is then translocated into nucleus. There is evidence of two distinct sized nuclear clusterin proteins (~50 kDa and ~60 kDa, Pajak et al., 2007), that could results from translation started either at ATG present in exon 3 or in exon 1, respectively. Clusterin proteins have never been crystallized, so the suggested protein structures are based on computational modeling.
Expression	Ubiquitous expression in various tissue types.
Localisation	The different clusterin protein isoforms localize to different cellular compartments. The nuclear clusterin translocated to nucleus after translation and glycosylation. The secreted clusterin is initially targeted to ER, and the glycosylated protein is eventually secreted. There is also evidence of stress-caused retention of sCLU in the cytosol instead of secretion (Nizard et al., 2007).
Function	The functions of clusterin in cells are not fully known. The controversiality of clusterin functions mainly results from the not well-established role of the two different protein isoforms with distinct subcellular localization and somewhat opposing functionalities. Some known functions include involvement in apoptosis through complexing with Ku70 autoantigen (nCLU, proapoptotic) or interfering with Bax-activation (sCLU, antiapoptotic) (Yang et al., 2000; Leskov et al., 2003; Zhang et al., 2005; Zhang et al., 2006). Clusterin has also been linked to spermatogenesis (Roberts et al., 1991), lipid transport (Jenne et al., 1991; Calero et al., 1994; Gelissen et al., 1998), epithelial cell differentiation (French et al., 1993; Schedin et al., 2000; Kim et al., 2007), TGF-beta signaling through Smad2/Smad3 (Lee et al., 2008), complement activation (Kirszbaum et al., 1992) and tumorigenesis (see below).
Homology	Homolog to murine Clu (75%), Homolog to rat Clu (77%), Low level homology to human clusterin-like 1 (retinal) (25%).

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