IHC staining of human colon cancer, using Anti-Hsp60 (clone: LK2)
All eukaryotes have several HSP60/CCT genes leading to the expression of compartment-specific isoforms fulfilling organelle-specific functions. They generally form two stacked rings of seven to nine subunits to build a barrel-shaped oligomer. While group I chaperonins of prokaryotes and eukaryotic organelles constitute two heptameric rings 79, the archaeal group II chaperonins constitute heptameric to nonameric rings with one to three different subunits 80. Eukaryotic group II chaperonins (CCTs) give rise to the hetero-oligomeric TCP-1 ring complex (TriC) consisting of two octameric rings 81. The eight subunit species are encoded by independent and highly diverged genes. These genes are calculated to have diverged around the starting point of the eukaryotic lineage and they are maintained in all eukaryotes investigated, suggesting a specific function for each subunit species 82, 83, 84. The amino acid sequences of these subunits share ≈30% identity 85 and a weak similarity to GroEL, Hsp60, and RBP 83. The primary structure harbors some highly conserved motifs probably responsible for ATPase function 83, implying this function is common to all subunits 82. Thus, each subunit is thought to have both specific and common functions 82. In recent years a wealth of evidence has been collected to demonstrate that TRiC functions as a complex protein folding machinery in the eukaryotic cytosol and that its chaperone activity is crucially involved in the folding and assembly of diverse de novo-synthesized proteins. These properties of TRiC may have evolved to facilitate the folding and assembly of highly evolved proteins in eukaryotic cells 85.
In the human cytosol, nine genes are known to encode the distinct subunits of TRiC. Two of them have been found to encode the zeta subunit of TRiC. While CCT6A encoding CCT-zeta 1 (Cct-6A) is constitutively expressed, CCT6B encoding CCT-zeta 2 (Cct-6B) is expressed only in testes 86. Interestingly, both genes are not heat-inducible. The CCT genes are conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito, C. elegans, S. cerevisiae, K. lactis, E. gossypii, S. pombe, M. oryzae, N. crassa, A. thaliana, rice, and frog. 117 – 136 organisms have orthologs with the human CCT genes. Alternate transcriptional splice variants of these genes encoding different isoforms have been observed and partly characterized. In addition, several pseudogenes of these genes have been located on different chromosomes. Table 2 enumerates the most common members of the HSP60/CPN60 family.
It is worth mentioning to highlight the presence of three further chaperonin-like genes in the human genome: BBS6 (also called MKKS), BBS10, and BBS12. Mutations in these genes have been shown to cause Bardet-Biedl syndrome (BBS) and/or the closely related McKusick-Kaufmann syndrome 87, 88, 89, 90. BBS is an autosomal recessive, clinically pleiotropic disorder characterized by progressive retinal degeneration, obesity, polydactyly, hypogenitalism, cognitive impairment, and kidney dysplasia 91, 92.