Disease relevance of TTC1

• Functional interaction of human immunodeficiency virus type 1 Vpu and Gag with a novel member of the tetratricopeptide repeat protein family [1].
• Identification of a novel cellular TPR-containing protein, SGT, that interacts with the nonstructural protein NS1 of parvovirus H-1 [2].
• Here we show that four proteins, namely the translationally controlled tumor protein, the human elongation factor 1-delta, tetratricopeptide repeat protein and the isoform 14-3-3-gamma of the 14-3-3-family are overexpressed in chemoresistant melanoma cell lines [3].
• 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 [4].
• Like Rickettsia felis, Orientia has many transposases and ankyrin and tetratricopeptide repeat domains [5].

Psychiatry related information on TTC1

• Recently, DYX1C1, a candidate gene for developmental dyslexia, encoding a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain, has been characterized through a translocation breakpoint in a Finnish family [6].

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

• The first, represented by cDNA tpr1, is located in chromosome 5q32-33 [11].
• The tetratricopeptide repeat (TPR) is a degenerate, repeating amino acid motif of 34 residues that has been identified in a variety of proteins; however, no biochemical function has been established for it [11].
• Molecular genetic maps were constructed for two full-sib populations, TTC1 and TTC2, derived from two Leymus triticoides x Leymus cinereus hybrids and one common Leymus triticoides tester [12].
• Within this 20-amino acid region, we have identified a consensus sequence motif that is also present in some other TPR cochaperones [13].
• Hop point mutations targeting a carboxylate clamp position in TPR1 disrupted Hsp70 binding, as was expected; however, similar point mutations in TPR2a or TPR2b also inhibited Hsp70 binding in some settings [14].

Anatomical context of TTC1

• PEX5 binds the PTS1 through its C-terminal 40-kDa tetratricopeptide repeat domain and is essential for import of PTS1-contining proteins into peroxisomes [15].
• Toc64 contains three tetratricopeptide repeat motifs that are exposed at the chloroplast cytosol interface [16].
• Tetratricopeptide repeat (TPR) motifs of p67(phox) participate in interaction with the small GTPase Rac and activation of the phagocyte NADPH oxidase [17].
• The mitochondrial import receptor translocase of the outer membrane of mitochondria (Tom20) consists of five segments, an N-terminal membrane-anchor segment, a linker segment rich in charged amino acids, a tetratricopeptide repeat motif, a glutamine-rich segment, and a C-terminal segment [18].
• 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 [19].

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].

References