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Gene Review

TTC1  -  tetratricopeptide repeat domain 1

Homo sapiens

Synonyms: TPR repeat protein 1, TPR1, Tetratricopeptide repeat protein 1
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Disease relevance of TTC1


Psychiatry related information on TTC1


High impact information on TTC1

  • Docking of tetratricopeptide repeat (TPR)-containing subunits indicates that they likely form a scaffold-like outer shell, mediating assembly of the complex and providing potential binding sites for regulators and substrates [7].
  • We report a cofactor in the p300 coactivator complex, Strap, which has an unusual structure, being composed almost entirely of a tandem series of six tetratricopeptide repeat (TPR) motifs [8].
  • While the respective tetratricopeptide repeat (TPR) domains of SGT1a and SGT1b control protein accumulation, they are dispensable for intrinsic functions of SGT1 in resistance and auxin responses [9].
  • The TPR domain engages with the catalytic channel of the phosphatase domain, restricting access to the catalytic site [10].
  • Here, we describe the structure of the autoinhibited state of Ppp5, revealing mechanisms of TPR-mediated phosphatase inhibition and Hsp90- and arachidonic acid-induced stimulation of phosphatase activity [10].

Biological context of TTC1


Anatomical context of TTC1


Associations of TTC1 with chemical compounds

  • These data show that immunophilin binding to hsp90 via TPR domains is conserved in the plant kingdom as well as in the animal kingdom and that geldanamycin will be an important tool for the study of hsp90-mediated protein chaperoning in plant cells [20].
  • A novel human protein serine/threonine phosphatase, which possesses four tetratricopeptide repeat motifs and localizes to the nucleus [21].
  • Mutational analyses revealed that a conserved leucine residue (Leu-64) on the third helix that would normally bind the fourth helix in an extended TPR is used to bind CHMP1B, raising the possibility that ESCRT-III proteins may bind by completing the TPR motif [22].
  • The C-terminal domain of Hsp90 displays independent chaperone activity, mediates dimerization, and contains the MEEVD motif essential for interaction with tetratricopeptide repeat-containing immunophilin cochaperones assembled in mature steroid receptor complexes [23].
  • Here we developed a novel assay to measure the activities of Galpha(12) and Galpha(13) by using glutathione S-transferase-fused tetratricopeptide repeat domain of Ser/Thr phosphatase type 5, taking advantage of the property that tetratricopeptide repeat domain strongly interacts with active forms of Galpha(12) and Galpha(13) [24].

Physical interactions of TTC1

  • However, despite these similarities, the TPR cochaperones have distinctive properties for binding Hsp90 and assembling with Hsp90.steroid receptor complexes [13].
  • This mutational analysis indicates that Hip's TPR is required for binding of Hip with hsp70's ATPase domain [25].
  • Here, we ask if wheat germ lysate also contains immunophilins of the FK506-binding class (FKBPs) that bind to the hsp90 component of the chaperone complex via tetratricopeptide repeat (TPR) domains [20].
  • Our results support a model in which the tetratricopeptide repeat domains of rapsyn bind directly to the cytoplasmic portion of MuSK, which could thereby serve as an initial scaffold for the clustering of acetylcholine receptors [26].
  • The ability of the immunophilin FKBP59-HBI to interact with the 90-kDa heat shock protein is encoded by its tetratricopeptide repeat domain [27].

Regulatory relationships of TTC1

  • Hsp40 and Hsp70 dependent folding of chemically denatured luciferase was enhanced by up to 80% when TPR1 was also present [28].
  • CHIP interacted with ASK1 in a TPR-dependent fashion and induced ubiquitylation and proteasome-dependent degradation of ASK1 [29].
  • These and related data support the view that the poly-TPR Clf1p splicing factor promotes the functional integration of the U4/U6.U5 tri-snRNP particle into the U1-, U2-dependent prespliceosome [30].
  • FKBP52 is a widely expressed FK506-binding immunophilin that possesses peptidylprolyl isomerase activity and a tetratricopeptide repeat involved in protein-protein interaction [31].

Other interactions of TTC1

  • In a two-hybrid screen for interaction with the GAP-related domain of neurofibromin, the product of the NF1 gene, we have identified two novel human genes encoding proteins with TPR motifs [11].
  • With the use of co-precipitation assays, we show here that the N-terminal TPR domain of mSTI1 without extensive flanking regions is both necessary and sufficient to mediate a specific interaction with hsc70 [32].
  • TPR1 mutations impaired Sti1p regulation of Hsp70, but deletion of TPR2a and TPR2b did not [33].
  • Binding of Hip to hsp70's ATPase domain was lost with deletions from the TPR and from an adjoining highly charged region; correspondingly, these Hip mutant forms were not recovered in receptor complexes [25].
  • Binding of immunophilins to the 90 kDa heat shock protein (hsp90) via a tetratricopeptide repeat domain is a conserved protein interaction in plants [20].

Analytical, diagnostic and therapeutic context of TTC1

  • In a search for additional tetratricopeptide repeat-containing proteins, we have identified a novel 35-kDa cytoplasmic protein, carboxyl terminus of Hsc70-interacting protein (CHIP) [34].
  • Investigation of the intracellular distribution of PP5 by immunofluorescence, using two different antibodies raised against the TPR and phosphatase domains, localizes PP5 predominantly to the nucleus [21].
  • We examined co-immunoprecipitation of hsp90 with wild type and mutant TPR constructs from transfected cells [35].
  • By combining equilibrium and kinetic fluorescent unfolding assays, with circular dichroism experiments, our study reveals that the unusual folding pathway of Tom70 is a consequence of the unfolding of two separate, autonomous TPR arrays, with the less stable region appearing to account for the low structural stability of Tom70 [36].
  • Using a carboxyl-terminal CyP40 construct as template, 24 amino acids from the TPR and flanking acidic and basic domains were individually mutated by site-directed mutagenesis, and the mutants were coexpressed in yeast with a carboxyl-terminal Hsp90beta construct and qualitatively assessed for binding using a beta-galactosidase filter assay [37].


  1. Functional interaction of human immunodeficiency virus type 1 Vpu and Gag with a novel member of the tetratricopeptide repeat protein family. Callahan, M.A., Handley, M.A., Lee, Y.H., Talbot, K.J., Harper, J.W., Panganiban, A.T. J. Virol. (1998) [Pubmed]
  2. Identification of a novel cellular TPR-containing protein, SGT, that interacts with the nonstructural protein NS1 of parvovirus H-1. Cziepluch, C., Kordes, E., Poirey, R., Grewenig, A., Rommelaere, J., Jauniaux, J.C. J. Virol. (1998) [Pubmed]
  3. Identification of novel proteins associated with the development of chemoresistance in malignant melanoma using two-dimensional electrophoresis. Sinha, P., Kohl, S., Fischer, J., Hütter, G., Kern, M., Köttgen, E., Dietel, M., Lage, H., Schnölzer, M., Schadendorf, D. Electrophoresis (2000) [Pubmed]
  4. TTC4, a novel human gene containing the tetratricopeptide repeat and mapping to the region of chromosome 1p31 that is frequently deleted in sporadic breast cancer. Su, G., Roberts, T., Cowell, J.K. Genomics (1999) [Pubmed]
  5. New Perspectives on Rickettsial Evolution from New Genome Sequences of Rickettsia, particularly R. canadensis, and Orientia tsutsugamushi. Eremeeva, M.E., Madan, A., Shaw, C.D., Tang, K., Dasch, G.A. Ann. N. Y. Acad. Sci. (2005) [Pubmed]
  6. No evidence for association between dyslexia and DYX1C1 functional variants in a group of children and adolescents from Southern Italy. Bellini, G., Bravaccio, C., Calamoneri, F., Donatella Cocuzza, M., Fiorillo, P., Gagliano, A., Mazzone, D., del Giudice, E.M., Scuccimarra, G., Militerni, R., Pascotto, A. J. Mol. Neurosci. (2005) [Pubmed]
  7. Structural analysis of the anaphase-promoting complex reveals multiple active sites and insights into polyubiquitylation. Passmore, L.A., Booth, C.R., Vénien-Bryan, C., Ludtke, S.J., Fioretto, C., Johnson, L.N., Chiu, W., Barford, D. Mol. Cell (2005) [Pubmed]
  8. A TPR motif cofactor contributes to p300 activity in the p53 response. Demonacos, C., Krstic-Demonacos, M., La Thangue, N.B. Mol. Cell (2001) [Pubmed]
  9. Role of SGT1 in resistance protein accumulation in plant immunity. Azevedo, C., Betsuyaku, S., Peart, J., Takahashi, A., Noël, L., Sadanandom, A., Casais, C., Parker, J., Shirasu, K. EMBO J. (2006) [Pubmed]
  10. Molecular basis for TPR domain-mediated regulation of protein phosphatase 5. Yang, J., Roe, S.M., Cliff, M.J., Williams, M.A., Ladbury, J.E., Cohen, P.T., Barford, D. EMBO J. (2005) [Pubmed]
  11. Identification and characterization of two novel tetratricopeptide repeat-containing genes. Murthy, A.E., Bernards, A., Church, D., Wasmuth, J., Gusella, J.F. DNA Cell Biol. (1996) [Pubmed]
  12. Molecular genetic linkage maps for allotetraploid Leymus wildryes (Gramineae: Triticeae). Wu, X., Larson, S.R., Hu, Z., Palazzo, A.J., Jones, T.A., Wang, R.R., Jensen, K.B., Chatterton, N.J. Genome (2003) [Pubmed]
  13. C-terminal sequences outside the tetratricopeptide repeat domain of FKBP51 and FKBP52 cause differential binding to Hsp90. Cheung-Flynn, J., Roberts, P.J., Riggs, D.L., Smith, D.F. J. Biol. Chem. (2003) [Pubmed]
  14. Multiple domains of the co-chaperone Hop are important for Hsp70 binding. Carrigan, P.E., Nelson, G.M., Roberts, P.J., Stoffer, J., Riggs, D.L., Smith, D.F. J. Biol. Chem. (2004) [Pubmed]
  15. PEX5 binds the PTS1 independently of Hsp70 and the peroxin PEX12. Harper, C.C., Berg, J.M., Gould, S.J. J. Biol. Chem. (2003) [Pubmed]
  16. Toc64, a new component of the protein translocon of chloroplasts. Sohrt, K., Soll, J. J. Cell Biol. (2000) [Pubmed]
  17. Tetratricopeptide repeat (TPR) motifs of p67(phox) participate in interaction with the small GTPase Rac and activation of the phagocyte NADPH oxidase. Koga, H., Terasawa, H., Nunoi, H., Takeshige, K., Inagaki, F., Sumimoto, H. J. Biol. Chem. (1999) [Pubmed]
  18. Functional analysis of human mitochondrial receptor Tom20 for protein import into mitochondria. Yano, M., Kanazawa, M., Terada, K., Takeya, M., Hoogenraad, N., Mori, M. J. Biol. Chem. (1998) [Pubmed]
  19. Binding of nicotinamide adenine dinucleotide phosphate to the tetratricopeptide repeat domains at the N-terminus of p67PHOX, a subunit of the leukocyte nicotinamide adenine dinucleotide phosphate oxidase. Dang, P.M., Johnson, J.L., Babior, B.M. Biochemistry (2000) [Pubmed]
  20. Binding of immunophilins to the 90 kDa heat shock protein (hsp90) via a tetratricopeptide repeat domain is a conserved protein interaction in plants. Owens-Grillo, J.K., Stancato, L.F., Hoffmann, K., Pratt, W.B., Krishna, P. Biochemistry (1996) [Pubmed]
  21. A novel human protein serine/threonine phosphatase, which possesses four tetratricopeptide repeat motifs and localizes to the nucleus. Chen, M.X., McPartlin, A.E., Brown, L., Chen, Y.H., Barker, H.M., Cohen, P.T. EMBO J. (1994) [Pubmed]
  22. Structure and ESCRT-III protein interactions of the MIT domain of human VPS4A. Scott, A., Gaspar, J., Stuchell-Brereton, M.D., Alam, S.L., Skalicky, J.J., Sundquist, W.I. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  23. Modulation of chaperone function and cochaperone interaction by novobiocin in the C-terminal domain of Hsp90: evidence that coumarin antibiotics disrupt Hsp90 dimerization. Allan, R.K., Mok, D., Ward, B.K., Ratajczak, T. J. Biol. Chem. (2006) [Pubmed]
  24. N-terminal short sequences of alpha subunits of the G12 family determine selective coupling to receptors. Yamaguchi, Y., Katoh, H., Negishi, M. J. Biol. Chem. (2003) [Pubmed]
  25. Mutational analysis of the hsp70-interacting protein Hip. Prapapanich, V., Chen, S., Toran, E.J., Rimerman, R.A., Smith, D.F. Mol. Cell. Biol. (1996) [Pubmed]
  26. The tetratricopeptide repeat domains of rapsyn bind directly to cytoplasmic sequences of the muscle-specific kinase. Antolik, C., Catino, D.H., Resneck, W.G., Bloch, R.J. Neuroscience (2006) [Pubmed]
  27. The ability of the immunophilin FKBP59-HBI to interact with the 90-kDa heat shock protein is encoded by its tetratricopeptide repeat domain. Radanyi, C., Chambraud, B., Baulieu, E.E. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  28. Cooperative interaction of Hsp40 and TPR1 with Hsp70 reverses Hsp70-HspBp1 complex formation. Oh, W.K., Song, J. Mol. Cells (2003) [Pubmed]
  29. C-terminus of heat shock protein 70--interacting protein facilitates degradation of apoptosis signal-regulating kinase 1 and inhibits apoptosis signal-regulating kinase 1--dependent apoptosis. Hwang, J.R., Zhang, C., Patterson, C. Cell Stress Chaperones (2005) [Pubmed]
  30. The Clf1p splicing factor promotes spliceosome assembly through N-terminal tetratricopeptide repeat contacts. Wang, Q., Hobbs, K., Lynn, B., Rymond, B.C. J. Biol. Chem. (2003) [Pubmed]
  31. Organization of the human FK506-binding immunophilin FKBP52 protein gene (FKBP4). Scammell, J.G., Hubler, T.R., Denny, W.B., Valentine, D.L. Genomics (2003) [Pubmed]
  32. Heat shock cognate protein 70 chaperone-binding site in the co-chaperone murine stress-inducible protein 1 maps to within three consecutive tetratricopeptide repeat motifs. Van Der Spuy, J., Kana, B.D., Dirr, H.W., Blatch, G.L. Biochem. J. (2000) [Pubmed]
  33. Independent regulation of Hsp70 and Hsp90 chaperones by Hsp70/Hsp90-organizing protein Sti1 (Hop1). Song, Y., Masison, D.C. J. Biol. Chem. (2005) [Pubmed]
  34. Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Ballinger, C.A., Connell, P., Wu, Y., Hu, Z., Thompson, L.J., Yin, L.Y., Patterson, C. Mol. Cell. Biol. (1999) [Pubmed]
  35. Identification of conserved residues required for the binding of a tetratricopeptide repeat domain to heat shock protein 90. Russell, L.C., Whitt, S.R., Chen, M.S., Chinkers, M. J. Biol. Chem. (1999) [Pubmed]
  36. Tracking the unfolding pathway of a multirepeat protein via tryptophan scanning: evidence of localized instability in the mitochondrial import receptor Tom70. Bushell, S.R., Bottomley, S.P., Rossjohn, J., Beddoe, T. J. Biol. Chem. (2006) [Pubmed]
  37. A structure-based mutational analysis of cyclophilin 40 identifies key residues in the core tetratricopeptide repeat domain that mediate binding to Hsp90. Ward, B.K., Allan, R.K., Mok, D., Temple, S.E., Taylor, P., Dornan, J., Mark, P.J., Shaw, D.J., Kumar, P., Walkinshaw, M.D., Ratajczak, T. J. Biol. Chem. (2002) [Pubmed]
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