Disease relevance of CCT

• Autoantibodies against chaperonin CCT in human sera with rheumatic autoimmune diseases: comparison with antibodies against other Hsp60 family proteins [1].
• Immunoabsorption experiments demonstrated that most of the autoantibodies recognizing CCT were cross-reactive with mitochondrial Hsp60, E coli GroEL, and mycobacterial Hsp65 [1].
• Two adenomas (14.3%) with undetectable APC alterations showed missense mutations at codon 45 (TCT to TTT or to CCT) in beta-catenin [2].
• Disruption of the CCT complex by RNAi-mediated knockdown enhanced Htt-polyQ aggregate formation and cellular toxicity [3].
• Liposuction+CCT removed the arm lymphedema completely, whereas CCT alone reduced it by half [4].

High impact information on CCT

• To define the basis of TRiC/CCT substrate recognition, we mapped the chaperonin interactions with the VHL tumor suppressor [5].
• Identification of the TRiC/CCT Substrate Binding Sites Uncovers the Function of Subunit Diversity in Eukaryotic Chaperonins [5].
• Here, we show that the hetero-oligomeric chaperonin TRiC (also known as CCT) physically interacts with polyglutamine-expanded variants of huntingtin (Htt) and effectively inhibits their aggregation [6].
• Similarly, overexpression of all eight subunits of CCT suppressed Htt aggregation and neuronal cell death [3].
• CCT (also called the TCP-1 complex or TriC) is a chaperonin found in the eukaryotic cytosol, and has unique structural and functional features [7].

Biological context of CCT

• Second, a number of tumor-derived missense mutations in exon II did not decrease CCT binding, and most had no detectable effect upon VCB-Cul2 assembly [8].
• When the size distributions of trinucleotide repeats were compared to previously reported data, significant differences were found for the CTT repeat, which corresponds to the expanded GAA repeat in Friedreich ataxia, as well as for ATT, CCT and GTT repeats [9].
• It has been previously demonstrated that nucleotide exchange and ATP hydrolysis act to switch CCT between conformations that interact either strongly or weakly with unfolded substrates [Melki, R., & Cowan, N.J. (1994) Mol. Cell. Biol. 14, 2895-2904] [10].
• The CCT promoter directs high-level transgene expression in distal lung epithelial cell lines [11].
• The TCP-1 ring complex (TRiC; also called CCT, for chaperonin containing TCP-1) is a large (approximately 900 kDa) multisubunit complex that mediates protein folding in the eukaryotic cytosol [12].

Anatomical context of CCT

• The chaperonin containing t-complex polypeptide 1 (TCP-1), as one of its subunits, CCT, is a cytosolic heterooligomeric molecular chaperone assisting in the folding of proteins in eukaryotic cytosol [13].
• It is first shown, by the use of a range of labeled denatured substrate proteins and a radiolabeled total soluble HeLa cell extract, that CCT in the absence of nucleotides can bind any of a large number of proteins in vitro with high affinity [10].
• Results suggest the hypothesis that downregulation of the CCT chaperonin in fetal wound may inhibit the formation of myofibroblasts, a cell type that correlates highly with scarring in postnatal wound healing, by preventing the folding of sufficient alpha-smooth muscle actin to form the stress fibers characteristic of these cells [14].
• We measured the latencies and amplitudes of individual wave deflections, peripheral and central conduction time (PCT and CCT) of spinal and cortical SEP.RESULTS: The examination proved and confirmed the elongation not only of peripheral conduction time but also of the central conduction time - especially in spinal cord structures [15].
• Assembly of the native alpha/beta tubulin heterodimer, the subunit that polymerizes to form microtubules, requires the participation of several molecular chaperones, namely prefoldin, the cytosolic chaperonin CCT, and a series of five tubulin-specific chaperones termed cofactors A-E (TBCA-E) [16].

Associations of CCT with chemical compounds

• In the affected males of kindred B, a G to C substitution was found at nucleotide 428, altering codon 143 from arginine (CGT) to proline (CCT) in the second cytoplasmic domain [17].
• While a decrease in the level of serum thyroid hormones, HDL-C and in hepatic glycogen content, was observed in CCT diet fed animals; it increased the concentration of other serum lipids, glucose and creatinine; ALP activity; tissue and serum LPO [18].
• However, following terazosin administration for 15 days to CCT diet fed animals, status of thyroid hormones and all other thyroid dependent parameters were reversed suggesting that the drug might be acting through an alteration in the thyroid functions [18].
• An association between human cancer risk and a single nucleotide polymorphism (SNP) at codon 50 of the AXIN2 gene, encoding either proline (CCT) or serine (TCT), remains undefined [19].
• Sequencing of the TR beta gene showed that the patient and her father had a codon 453 mutation resulting in a CCT (proline) to ACT (threonine) substitution [20].

Physical interactions of CCT

• We conclude that the selection pressure to mutate VHL exon II during tumorigenesis does not relate to loss of CCT binding but may reflect quantitative or qualitative defects in HIF binding and/or in pVHL-dependent ubiquitin ligase activity [8].
• Second, by the use of denatured labeled beta-actin and beta-tubulin as model substrates for binding to CCT, we demonstrate that the CCT particle can contain two substrate protein chains simultaneously [10].
• We show for the first time in protozoa that beta-tubulin folding is assisted by CCT and requires cofactor A. In addition, we observed that E. focardiibeta-T1 competes with human beta5 tubulin isotype for binding to CCT [21].

Other interactions of CCT

• CCT theta also contains the motifs common to all the other subunits of CCT which are postulated to be involved in ATPase activity [13].
• The Hsp70 and TRiC/CCT chaperone systems cooperate in vivo to assemble the von Hippel-Lindau tumor suppressor complex [22].
• Thus, CCT likely functions, at least in part, by retaining VHL chains pending the availability of elongin B/C for final folding and/or assembly [8].
• In the second one, the 4 explored PTs showed a slowed conduction, but in addition, CMCT difference between the CLT and CCT was longer than normal [23].
• Lebrón, Managing Editor, CCT, AAAS, 1333 H Street, NW, Washington, DC 20005 USA, FAX 202-842-2868 [24].

Analytical, diagnostic and therapeutic context of CCT

• Third, by electron microscopy, sedimentation velocity, and intrinsic fluorescence measurements, we document the conformational difference between CCT in its ATP- and ADP-bound forms, as well as the change that results from binding of substrate protein [10].
• Electrophoretic mobility shift assay demonstrated that the DNA sequences with the CCT repeats formed complexes with nuclear factors, containing, at least, Sp1 and Sp3 [25].
• BACKGROUND: Cardiac CT (CCT) and real-time 3D echocardiography (RT3DE) are being used increasingly in clinical cardiology [26].
• CCT and ECG were normal [27].
• Neurologic examination and CCT-scan were performed [28].

References