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Gene Review

PTRH2  -  peptidyl-tRNA hydrolase 2

Homo sapiens

Synonyms: BIT1, Bcl-2 inhibitor of transcription 1, CFAP37, CGI-147, PTH 2, ...
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Disease relevance of PTRH2

  • In contrast to the structure of Escherichia coli Pth, H. sapiens Pth2 has an alpha/beta fold with a four-stranded antiparallel beta-sheet in its core surrounded by two alpha-helices on each side [1].
  • Among the most potent inhibitors of human cytomegalovirus protease identified by random screening of a chemical library was 1,4-dihydro-7,8-dimethyl 6H-pyrimido[1,2-b]-1,2,4,5-tetrazin-6-one (1) (PTH2) [2].

High impact information on PTRH2

  • Cell attachment to fibronectin counteracts the apoptotic effect of Bit1 and AES [3].
  • A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors [3].
  • Increasing Bit1 expression enhances anoikis, while suppressing the expression reduces it [3].
  • In addition, intermolecular contacts in the crystal asymmetric unit cell suggest a likely surface for protein-protein interactions related to the Pth2-mediated apoptosis [1].
  • The recently identified natural peptide ligand, tuberoinfundibular peptide of 39 residues (TIP39) for the parathyroid hormone-2 (PTH2) receptor has been structurally characterized by high resolution NMR, circular dichroism, and computer simulations [4].

Biological context of PTRH2

  • Another layer of complexity is added by the recently discovered PTH2-Rc subtype displaying unique tissue distribution and ligand specificity, and the potential presence in mammals of a third receptor subtype [5].

Anatomical context of PTRH2

  • However, only [Ile5]PTHrP-(1-34), and not [His5]PTH-(1-34), binds to and stimulates cAMP accumulation and the release of cytosolic free calcium in HEK293/BP-16, a clonal human embryonic kidney cell line stably expressing the recombinant hPTH2 receptor [6].
  • To better understand the molecular basis for these processes, we first prepared a series of [I5,W23,Y36]-PTHrP(1-36)NH2 analogs having stepwise deletions of residues 1-4 and characterized them with the human (h)PTH-1 and hPTH-2 receptor subtypes stably transfected in LLC-PK1 cells [7].
  • PTH2 receptors are present in several central nervous system and peripheral areas and are particularly concentrated in the hypothalamus, limbic areas and the outer layers of the spinal cord dorsal horn [8].

Associations of PTRH2 with chemical compounds

  • The mechanism of the specificity "switch" remains to be elucidated, but may result from a subtle perturbation of the bioactive conformation and/or from a direct steric hindrance at the hPTH2 receptor-ligand interface created by histidine at position 5 [6].
  • We have successfully developed and used a novel expression cloning strategy to isolate the integrin-regulated apoptosis signaling protein BIT-1 [9].

Other interactions of PTRH2

  • The hPTH2, but not the hPTH/PTHrP, receptor can discriminate between the two hormones based on the structural differences generated at position 5 [6].
  • We have generated a series of stably transfected HEK-293 cell lines expressing the newly identified alternate human PTH receptor (hPTH2 receptor) [10].
  • These results demonstrate that the 1-5 region of [I5,W23]-PTHrP(1-36) is critical for activating the PTH-1 and PTH-2 receptors and suggest that the individual residues in this region play distinct roles in modulating the activation states of the two receptors [7].
  • Activation of PKD enhances Bit1 function in anoikis, whereas inhibiting PKD function with pharmacological inhibitors or small interfering RNA compromises the ability of Bit1 to induce anoikis [11].


  1. Crystal structure of a human peptidyl-tRNA hydrolase reveals a new fold and suggests basis for a bifunctional activity. De Pereda, J.M., Waas, W.F., Jan, Y., Ruoslahti, E., Schimmel, P., Pascual, J. J. Biol. Chem. (2004) [Pubmed]
  2. Flavins inhibit human cytomegalovirus UL80 protease via disulfide bond formation. Baum, E.Z., Ding, W.D., Siegel, M.M., Hulmes, J., Bebernitz, G.A., Sridharan, L., Tabei, K., Krishnamurthy, G., Carofiglio, T., Groves, J.T., Bloom, J.D., DiGrandi, M., Bradley, M., Ellestad, G., Seddon, A.P., Gluzman, Y. Biochemistry (1996) [Pubmed]
  3. A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors. Jan, Y., Matter, M., Pai, J.T., Chen, Y.L., Pilch, J., Komatsu, M., Ong, E., Fukuda, M., Ruoslahti, E. Cell (2004) [Pubmed]
  4. Structure of tuberoinfundibular peptide of 39 residues. Piserchio, A., Usdin, T., Mierke, D.F. J. Biol. Chem. (2000) [Pubmed]
  5. Parathyroid hormone 1 receptor: insights into structure and function. Chorev, M. Recept. Channels (2002) [Pubmed]
  6. Histidine at position 5 is the specificity "switch" between two parathyroid hormone receptor subtypes. Behar, V., Nakamoto, C., Greenberg, Z., Bisello, A., Suva, L.J., Rosenblatt, M., Chorev, M. Endocrinology (1996) [Pubmed]
  7. Studies of the N-terminal region of a parathyroid hormone-related peptide (1-36) analog: receptor subtype-selective agonists, antagonists, and photochemical cross-linking agents. Carter, P.H., Jüppner, H., Gardella, T.J. Endocrinology (1999) [Pubmed]
  8. Emerging functions for tuberoinfundibular peptide of 39 residues. Usdin, T.B., Dobolyi, A., Ueda, H., Palkovits, M. Trends Endocrinol. Metab. (2003) [Pubmed]
  9. Expression cloning of signaling proteins regulated by cell adhesion. Matter, M.L., Ramos, J.W. Methods Mol. Biol. (2006) [Pubmed]
  10. The human PTH2 receptor: binding and signal transduction properties of the stably expressed recombinant receptor. Behar, V., Pines, M., Nakamoto, C., Greenberg, Z., Bisello, A., Stueckle, S.M., Bessalle, R., Usdin, T.B., Chorev, M., Rosenblatt, M., Suva, L.J. Endocrinology (1996) [Pubmed]
  11. Protein kinase D is a positive regulator of Bit1 apoptotic function. Biliran, H., Jan, Y., Chen, R., Pasquale, E.B., Ruoslahti, E. J. Biol. Chem. (2008) [Pubmed]
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