Alternative titles; symbols
HGNC Approved Gene Symbol: TRAP1
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38) : 16:3,658,037-3,717,524 (from NCBI)
HSP90 proteins are highly conserved molecular chaperones that have key roles in signal transduction, protein folding, protein degradation, and morphologic evolution. HSP90 proteins normally associate with other cochaperones and play important roles in folding newly synthesized proteins or stabilizing and refolding denatured proteins after stress. TRAP1 is a mitochondrial HSP90 protein. Other HSP90 proteins are found in cytosol (see HSP90AA1; 140571) and endoplasmic reticulum (HSP90B1; 191175) (Chen et al., 2005).
Using a yeast 2-hybrid screen of a Gal4/HeLa cDNA library with the intracellular domain of TNFR1 (191190) as bait, followed by 5-prime RACE, Song et al. (1995) isolated a partial cDNA encoding TRAP1. The deduced 661-amino acid protein is 60% similar to HSP90 family members, although it lacks the highly charged domain found in HSP90 proteins. Northern blot analysis revealed variable but ubiquitous expression of a 2.7-kb TRAP1 transcript.
By yeast 2-hybrid screening of several cDNA libraries with an N-terminally truncated retinoblastoma protein (RB1; 614041) as bait, Chen et al. (1996) obtained a nearly complete cDNA encoding TRAP1, which they termed HSP75. HSP75 has 698 amino acids. Immunoprecipitation, immunoblot analysis, and immunofluorescence microscopy demonstrated expression of a 75-kD cytoplasmic protein that colocalized with RB1 during mitosis but not during other phases. During heat shock, HSP75 migrated to the nucleus.
In a yeast 2-hybrid screen with exostosin-2 (EXT2; 608210) as bait, Simmons et al. (1999) isolated TRAP1. They reported that the full-length cDNA sequence encodes a 704-amino acid protein (GenBank AF154108).
Using immunofluorescence microscopy, Felts et al. (2000) demonstrated a mitochondrial localization for TRAP1. TRAP1 possesses a mitochondrial localization sequence, STQTAED, beginning after cleavage at position 59. Sequence analysis predicted that TRAP1 is 54% identical to a Drosophila homolog.
By database analysis, Chen et al. (2005) identified several TRAP1 variants. Like other HSP90 proteins, the 704-amino acid TRAP1 protein has a highly conserved N-terminal domain, a middle domain involved in ATPase activity, a charged domain, and a C-terminal domain, but it lacks the charged domain found immediately after the N-terminal domain in other HSP90 proteins. It also has a signal peptide and gln-rich region.
Using yeast 2-hybrid and GST pull-down analyses, Song et al. (1995) found that TRAP1 interacted with the N-terminal half of TNFR1.
Binding analysis by Chen et al. (1996) showed that HSP75 used an LxCxE motif to bind to the T antigen-binding domains of RB1. Western blot analysis indicated that HSP75 could refold denatured RB1, suggesting that HSP75 acts as a chaperone for RB1.
Binding analysis by Simmons et al. (1999) showed that TRAP1 interacted with the C-terminal ends of the proteins encoded by both multiple exostoses-causing genes, EXT1 (608177) and EXT2, but not with EXTL1 (601738) or EXTL3 (605744). The interaction required the presence of a his residue in the EXT proteins, the loss of which had been identified in a single family with type I multiple exostoses (133700) by Raskind et al. (1998).
Felts et al. (2000) reported that TRAP1 lacked the chaperone activities of HSP90 and also failed to interact with cochaperones of HSP90. However, TRAP1 did bind ATP and expressed an ATPase activity that could be blocked by the HSP90 inhibitor geldanamycin.
Chen et al. (2005) determined that the TRAP1 gene contains 19 exons.
Simmons et al. (1999) stated that the TRAP1 gene maps to chromosome 16.
By genomic sequence analysis, Chen et al. (2005) mapped the TRAP1 gene to chromosome 16p13.3.
Chen et al. (2005) provided a revised nomenclature system for the HSP90 gene family. Under this system, the root HSP90A indicates cytosolic HSP90, HSP90B indicates endoplasmic reticulum HSP90, and TRAP indicates mitochondrial HSP90. HSP90A was divided into 2 classes, with HSP90AA representing conventional HSP90-alpha, and HSP90AB representing HSP90-beta. The number following the root/class represents the gene in that class, and a 'P' at the end indicates a putative pseudogene. Chen et al. (2005) also proposed the alias HSP90L for TRAP1.
Chen, B., Piel, W. H., Gui, L., Bruford, E., Monteiro, A. The HSP90 family of genes in the human genome: insights into their divergence and evolution. Genomics 86: 627-637, 2005. [PubMed: 16269234] [Full Text: https://doi.org/10.1016/j.ygeno.2005.08.012]
Chen, C.-F., Chen, Y., Dai, K., Chen, P.-L., Riley, D. J., Lee, W.-H. A new member of the hsp90 family of molecular chaperones interacts with the retinoblastoma protein during mitosis and after heat shock. Molec. Cell. Biol. 16: 4691-4699, 1996. [PubMed: 8756626] [Full Text: https://doi.org/10.1128/MCB.16.9.4691]
Felts, S. J., Owen, B. A. L., Nguyen, P., Trepel, J., Donner, D. B., Toft, D. O. The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. J. Biol. Chem. 275: 3305-3312, 2000. [PubMed: 10652318] [Full Text: https://doi.org/10.1074/jbc.275.5.3305]
Raskind, W. H., Conrad, E. U., III, Matsushita, M., Wijsman, E. M., Wells, D. E., Chapman, N., Sandell, L. J., Wagner, M., Houck, J. Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses. Hum. Mutat. 11: 231-239, 1998. [PubMed: 9521425] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)11:3<231::AID-HUMU8>3.0.CO;2-K]
Simmons, A. D., Musy, M. M., Lopes, C. S., Hwang, L.-Y., Yang, Y.-P., Lovett, M. A direct interaction between EXT proteins and glycosyltransferases is defective in hereditary multiple exostoses. Hum. Molec. Genet. 8: 2155-2164, 1999. [PubMed: 10545594] [Full Text: https://doi.org/10.1093/hmg/8.12.2155]
Song, H. Y., Dunbar, J. D., Zhang, Y. X., Guo, D., Donner, D. B. Identification of a protein with homology to hsp90 that binds the type 1 tumor necrosis factor receptor. J. Biol. Chem. 270: 3574-3581, 1995. [PubMed: 7876093]