Disease relevance of Hspd1

• Mycobacterium tuberculosis chaperonin 10 stimulates bone resorption: a potential contributory factor in Pott's disease [1].
• CONCLUSIONS: These results suggest that the simultaneous expression of these two proteins that form a chaperonin complex in the mitochondria plays an important role in the survival of myogenic cells after ischemia/reperfusion injury [2].
• This protein is a member of the chaperonin family, which includes Escherichia coli GroEL, the mitochondrial heat-shock protein Hsp60, the plastid Rubisco-subunit-binding protein and the archaebacterial protein TF55 [3].
• Mycobacterium tuberculosis chaperonin 10 is secreted in the macrophage phagosome: is secretion due to dissociation and adoption of a partially helical structure at the membrane [4]?
• We previously reported that chaperonin 60 proteins from Gram-negative bacteria, but not mycobacteria, have the capacity to resorb cultured murine calvarial bone [5].

High impact information on Hspd1

• The chaperonin GroEL is able to mediate protein folding in its central cavity [6].
• Folding of the major cytoskeletal components in the cytosol of mammalian cells is mediated by interactions with t-complex polypeptide-1 (TCP1) molecular chaperones, a situation analogous to the chaperonin 60-aided folding of polypeptides in bacteria, chloroplasts and mitochondria [7].
• Here we report for the first time that a protein, identified by a monoclonal antibody to be the Mt heat shock protein (Baird, P.N., L.M. Hall, and A.R.M. Coates. 1989. J. Gen. Microbiol. 135:931-939) chaperonin (cpn) 10, is responsible for the osteolytic activity of this bacterium [1].
• Here we find that upon ATP binding, mimicked by the non-hydrolysable analog AMP-PNP (5'-adenylyl-imido-diphosphate), to both CCT-alpha-actin and CCT- beta-tubulin complexes, the chaperonin component undergoes concerted movements of the apical domains, resulting in the cavity being closed off by the helical protrusions of the eight apical domains [8].
• Structure of a trimeric domain of the MHC class II-associated chaperonin and targeting protein Ii [9].

Biological context of Hspd1

• With the introduction of few gaps, the amino acid sequence of TCP-1 shows between 60-63% similarity (17-20% identical residues and 42-45% conserved substitutions) throughout its length to various chaperonin proteins, indicating a common evolutionary origin [10].
• Protein folding. Cytosolic chaperonin confirmed [11].
• The eukaryotic, cytoplasmic chaperonin, CCT, is essential for the biogenesis of actin- and tubulin-based cytoskeletal structures [12].
• The cytosolic chaperonin CCT associates to cytoplasmic microtubular structures during mammalian spermiogenesis and to heterochromatin in germline and somatic cells [13].
• A conserved sequence segment of PrP (residues 90-121), critical for PrP(Sc) generation in vivo, is also required for chaperonin-mediated aggregate formation in vitro [14].

Anatomical context of Hspd1

• The chaperonin CCT hexadecamer is required for the folding of non-native actins and tubulins in eukaryotic cells [15].
• The type II chaperonin CCT (chaperonin containing Tcp-1) of eukaryotic cytosol is a heteromeric 16-mer particle composed of eight different subunits [16].
• Edman degradation reveals that the initiator Met residue of the recombinant protein is removed in vivo, similar to the authentic chaperonin 10 purified from rat liver mitochondria [17].
• Selected subunits of the cytosolic chaperonin associate with microtubules assembled in vitro [18].
• Cytoplasmic chaperonin complexes enter neurites developing in vitro and differ in subunit composition within single cells [19].

Associations of Hspd1 with chemical compounds

• In this study, by generating transgenic mice expressing truncated Ii lacking its luminal domain, we could dissect the chaperonin activity of Ii from its role in B cell maturation [20].
• Aggregates form upon ATP-dependent release of PrP from chaperonin and have certain properties of PrP(Sc), including a high beta-sheet content, the ability to bind the dye Congo red, detergent-insolubility and increased protease-resistance [14].
• It is different from PAF or chaperonin 10 [21].
• An additional 16 protein spots including glutathione S-transferase subclass, apolipoprotein E and chaperonin proteins were changed in both strains [22].

Physical interactions of Hspd1

• Analysis of the nascent translation products for folding intermediates has identified a major intermediate that contains all three myosin subunits in a complex with the eukaryotic cytosolic chaperonin [23].
• The receptor-associated protein, RAP, is a chaperonin-like molecule that binds to two members of the low density lipoprotein receptor (LDLR) superfamily-megalin (gp330) and the LDL receptor-related protein (LRP) [24].

Other interactions of Hspd1

• Sequence and structural homology between a mouse T-complex protein TCP-1 and the 'chaperonin' family of bacterial (GroEL, 60-65 kDa heat shock antigen) and eukaryotic proteins [10].
• Here we show that actin-RPV and gamma-tubulin are both folded via interaction with the same chaperonin that mediates the folding of beta-actin and alpha- and beta-tubulin [25].
• A Tetrahymena orthologue of the mouse chaperonin subunit CCT gamma and its coexpression with tubulin during cilia recovery [26].
• More important, like the authentic protein purified from mitochondria, the recombinant mitochondrial chaperonin 10, but not groES, is functionally compatible with the heptameric chaperonin 60 of mammalian mitochondria [17].
• Chaperonin-mediated de novo generation of prion protein aggregates [14].

Analytical, diagnostic and therapeutic context of Hspd1

• Sequence analysis of four candidate genes in this interval revealed a 1349G>A mutation in the chaperonin (delta) subunit 4 (Cct4) gene associated with the mf mutant [27].
• In analogy to GroEL, changes in shape of the cytosolic chaperonin have been detected in the presence of MgATP using electron microscopy but, in contrast to the nucleotide-induced conformational changes in GroEL, no details are available about the specific nature of these changes [28].
• The three-dimensional reconstruction of apo-CCT-alpha-actin by cryoelectron microscopy shows that actin binds either the CCTbeta-CCTdelta or the CCTepsilon-CCTdelta subunit pairs of the chaperonin in an open and apparently quasi-native conformation [29].
• Investigations with the latter confirmed that chaperonin 10 is the moiety in pregnancy serum which initiates response in the EPF bioassay [30].
• Molecular cloning and characterization of a group II chaperonin delta-subunit from soybean [31].

References