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Gene Review

TIMELESS  -  timeless circadian clock

Homo sapiens

Synonyms: Protein timeless homolog, TIM, TIM1, TIMELESS1, hTIM


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Disease relevance of TIMELESS

  • Analysis of cerebrospinal fluid mononuclear cells obtained from patients with multiple sclerosis revealed significantly higher mRNA expression of TIM-1 compared with controls [1].
  • To test the validity of these alternative interpretations for the stopped-flow burst-phase reaction in the (betaalpha)8, TIM barrel motif, a series of alanine replacements were made at five different leucine or isoleucine residues in the alpha subunit of tryptophan synthase (alphaTS) from Escherichia coli [2].
  • Here we report the first high-resolution crystal structure of ACMSD from Pseudomonas fluorescens which validates our previous predictions that this enzyme is a member of the metal-dependent amidohydrolase superfamily of the (beta/alpha)(8) TIM barrel fold [3].
  • We examined the expression of TIM-1 and -3 mRNAs in rat MBP(63-88)-induced experimental autoimmune encephalomyelitis (EAE) [4].
  • These results are the first to suggest that TIM-1 antibody may serve as a potent adjuvant in the development of new influenza virus vaccines [5].
  • The human TIMELESS gene was first cloned and named by homology to a fruit fly gene known as TIMELESS which controlled the circadian clock.  [6] Further study of human TIMELESS showed that it was a component of a DNA damage cell cycle checkpoint that regulated DNA replication and was orthologous to the yeast checkpoint genes SWI1 and TOF1[7] The human TIMELESS protein and the yeast proteins are stabilized by interaction with a second protein known as TIPIN (H. sapiens), SWI3 (S. pombe) or CSM3 (S. cerevisiae).  [8] 
  • In mammalian cells the TIMELESS/TIPIN complex appears to act at DNA replication forks to mediate interactions between two essential gene products, ATR and CHK1, which enforce checkpoints that stabilize stalled DNA replication forks, slow the rate of DNA replication and delay mitosis when replication is incomplete.  [9] [10] The yeast heterodimeric complexes perform the same tasks. Further study of fruit flies revealed a homologous gene known as TIMEOUT which may encode a replication fork protection factor.  [11] 
  • Human TIMELESS is not in the TIM (T cell, immunoglobulin, mucin-domain containing molecules) gene family. [12]

Psychiatry related information on TIMELESS 

  • Effects of temperature elevation on the molecular clock mechanisms have been shown in Neurospora (induction of the frequency (FRQ) protein) and in Drosophila (degradation of the period (PER) and timeless (TIM) protein) and can explain observed phase shifts of rhythms in conidiation and locomotor activity, respectively [13].

High impact information on TIMELESS

  • These protein interactions promote cyclical gene expression because heterodimers are observed only at high concentrations of per and tim RNA, separating intervals of RNA accumulation from times of PER/TIM complex activity [14].
  • These T cell subsets are primarily differentiated on the basis of the cytokines that they produce, however, we have identified a novel gene family called TIM (T cell, immunoglobulin, mucin domain-containing molecules), whose members are differentially expressed on Th1 and Th2 cells [15].
  • Genomic association of the TIM family and polymorphisms in both Tim-1 and Tim-3 in different immune-mediated diseases suggest that the family may have an important role in regulating immunity, both in terms of normal immune responses and in diseases like autoimmunity and asthma [15].
  • Cryptochrome (CRY), a photoreceptor for the circadian clock in Drosophila, binds to the clock component TIM in a light-dependent fashion and blocks its function [16].
  • Three multimeric protein complexes have been identified that import precursor proteins destined for the mitochondria: the TOM complex in the outer membrane and two TIM complexes in the inner membrane [17].

Chemical compound and disease context of TIMELESS


Biological context of TIMELESS

  • Finally, hTIM and mPER1 specifically inhibit CLOCK-BMAL1-induced transactivation of the mPer1 promoter [20].
  • Although the import machinery of the outer membrane can insert and translocate a few proteins on its own, completion of translocation o f most preproteins is dependent upon coupling to both the membrane potential and mt-Hsp70/ATP-driven transport across the inner membrane, mediated by the TIM complex [21].
  • The model is supported by the similarity with analogous TIM barrel structures of functionally related proteins, by the localization of catalytic amino acids at the active site, and by the coincidence between the shape of the substrate (HMG-CoA) and the predicted inner cavity [22].
  • This activity requires TIM-1 tyrosine phosphorylation [23].
  • Tipin was originally isolated as a protein interacting with Timeless/Tim1/Tim (Tim), which is known to be involved in both circadian rhythm and cell cycle checkpoint regulation [24].

Anatomical context of TIMELESS

  • The translocase of the outer mitochondrial membrane (TOM) and the translocases of the inner mitochondrial membrane (TIM) mediate these processes [25].
  • Mitochondrial function also requires import of proteins from the cytosol via the translocase of the outer and inner membrane (TOM and TIM complexes) [26].
  • A member of Tim family, TIM-1, is considered as a membrane protein that is associated with the development of Th2 biased immune responses and selectively expressed on Th2 cells [27].
  • These studies suggest that TIM-1 can regulate macrophage activation and alter the co-stimulatory properties of macrophages and thus may contribute to allergic inflammatory diseases such as asthma [28].
  • A member of TIM family, TIM-3 is selectively expressed on the surface of differentiated Th1 cells [29].

Associations of TIMELESS with chemical compounds

  • Structural (betaalpha)8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase [22].
  • Crystal structures of two bacterial 3-hydroxy-3-methylglutaryl-CoA lyases suggest a common catalytic mechanism among a family of TIM barrel metalloenzymes cleaving carbon-carbon bonds [30].
  • The portion of the interface of TcTIM that binds the benzothiazole derivative and its equivalent region in human TIM differs in amino acid composition and hydrophobic packing [31].
  • Agents that interact with their interface Cys inhibit TcTIM and TbTIM; and those TIMs that lack this Cys (such as human TIM) are largely or completely insensitive to these agents [32].
  • Specific structure appears at the N terminus in the sub-millisecond folding intermediate of the alpha subunit of tryptophan synthase, a TIM barrel protein [2].

Other interactions of TIMELESS

  • The TAPR locus containing the TIM gene family is implicated in the development of atopic inflammation in mouse, and TIM-1 allelic variation has been associated with the incidence of atopy in human patient populations [33].

Analytical, diagnostic and therapeutic context of TIMELESS

  • CONCLUSIONS: TIM-1 is a powerful tool for supplying valuable information about the effects of various gastrointestinal conditions on biopharmaceutical behavior and efficacy of drug delivery systems in the development of oral formulations [18].
  • Finally, vaccination with inactivated influenza virus with TIM-1 antibody results in the significant (P < 0.001) induction of proliferation and IFN-gamma production upon stimulation with one of three serologically distinct strains [5].
  • On the whole, the present study reveals that the weak interactions contribute to the global stability of (alpha/beta)(8) TIM-barrel proteins in an environment-specific manner, which can possibly be exploited for protein engineering applications [34].
  • Using western blot, immunofluorescence and enzymatic activity, we demonstrate that high accumulation of tau-crystallin and TIM starts in the late embryonic development (after the 24th stage of embryonic development) with maximum expression in a two-week posthatched animal [35].
  • Expression of JET along with the circadian photoreceptor cryptochrome (CRY) in cultured S2R cells confers light-dependent degradation onto TIM, thereby reconstituting the acute response + of the circadian clock to light in a cell culture system [36].


  1. T Cell Ig- and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis. Khademi, M., Illés, Z., Gielen, A.W., Marta, M., Takazawa, N., Baecher-Allan, C., Brundin, L., Hannerz, J., Martin, C., Harris, R.A., Hafler, D.A., Kuchroo, V.K., Olsson, T., Piehl, F., Wallström, E. J. Immunol. (2004) [Pubmed]
  2. Specific structure appears at the N terminus in the sub-millisecond folding intermediate of the alpha subunit of tryptophan synthase, a TIM barrel protein. Wu, Y., Vadrevu, R., Yang, X., Matthews, C.R. J. Mol. Biol. (2005) [Pubmed]
  3. Crystal structure of alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase: insight into the active site and catalytic mechanism of a novel decarboxylation reaction. Martynowski, D., Eyobo, Y., Li, T., Yang, K., Liu, A., Zhang, H. Biochemistry (2006) [Pubmed]
  4. Expression of T cell immunoglobulin- and mucin-domain-containing molecules-1 and -3 (TIM-1 and -3) in the rat nervous and immune systems. Gielen, A.W., Lobell, A., Lidman, O., Khademi, M., Olsson, T., Piehl, F. J. Neuroimmunol. (2005) [Pubmed]
  5. Vaccination with cell immunoglobulin mucin-1 antibodies and inactivated influenza enhances vaccine-specific lymphocyte proliferation, interferon-gamma production and cross-strain reactivity. Soo Hoo, W., Jensen, E.R., Saadat, A., Nieto, D., Moss, R.B., Carlo, D.J., Moll, T. Clin. Exp. Immunol. (2006) [Pubmed]
  6. A time-less function for mouse timeless. Gotter, A.L., Manganaro, T., Weaver, D.R., Kolakowski LF, J.r., Possidente, B., Sriram, S., MacLaughlin, D.T., Reppert, S.M. Nat. Neurosci. (2000) [Pubmed]
  7. Coupling of human circadian and cell cycles by the timeless protein. Unsal-Kaçmaz, K., Mullen, T.E., Kaufmann, W.K., Sancar, A. Mol. Cell. Biol. (2005) [Pubmed]
  8. Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors. Gotter, A.L., Suppa, C., Emanuel, B.S. J. Mol. Biol. (2007) [Pubmed]
  9. The human Tim/Tipin complex coordinates an Intra-S checkpoint response to UV that slows replication fork displacement. Unsal-Kaçmaz, K., Chastain, P.D., Qu, P.P., Minoo, P., Cordeiro-Stone, M., Sancar, A., Kaufmann, W.K. Mol. Cell. Biol. (2007) [Pubmed]
  10. The many facets of the Tim-Tipin protein families' roles in chromosome biology. McFarlane, R.J., Mian, S., Dalgaard, J.Z. Cell. Cycle. (2010) [Pubmed]
  11. Drosophila timeless2 is required for chromosome stability and circadian photoreception. Benna, C., Bonaccorsi, S., Wülbeck, C., Helfrich-Förster, C., Gatti, M., Kyriacou, C.P., Costa, R., Sandrelli, F. Curr. Biol. (2010) [Pubmed]
  12. TIM family of genes in immunity and tolerance. Kuchroo, V.K., Meyers, J.H., Umetsu, D.T., DeKruyff, R.H. Adv. Immunol. (2006) [Pubmed]
  13. Temperature effect on entrainment, phase shifting, and amplitude of circadian clocks and its molecular bases. Rensing, L., Ruoff, P. Chronobiol. Int. (2002) [Pubmed]
  14. The molecular control of circadian behavioral rhythms and their entrainment in Drosophila. Young, M.W. Annu. Rev. Biochem. (1998) [Pubmed]
  15. TIM Family of Genes in Immunity and Tolerance. Kuchroo, V.K., Meyers, J.H., Umetsu, D.T., Dekruyff, R.H. Adv. Immunol. (2006) [Pubmed]
  16. Light-independent role of CRY1 and CRY2 in the mammalian circadian clock. Griffin, E.A., Staknis, D., Weitz, C.J. Science (1999) [Pubmed]
  17. How mitochondria import hydrophilic and hydrophobic proteins. Chacinska, A., Pfanner, N., Meisinger, C. Trends Cell Biol. (2002) [Pubmed]
  18. A dynamic artificial gastrointestinal system for studying the behavior of orally administered drug dosage forms under various physiological conditions. Blanquet, S., Zeijdner, E., Beyssac, E., Meunier, J.P., Denis, S., Havenaar, R., Alric, M. Pharm. Res. (2004) [Pubmed]
  19. Economic evaluation of triflusal and aspirin in the treatment of acute myocardial infarction. Darbà, J., Izquierdo, I., Pontes, C., Navas, C., Rovira, J. PharmacoEconomics. (2002) [Pubmed]
  20. Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription. Sangoram, A.M., Saez, L., Antoch, M.P., Gekakis, N., Staknis, D., Whiteley, A., Fruechte, E.M., Vitaterna, M.H., Shimomura, K., King, D.P., Young, M.W., Weitz, C.J., Takahashi, J.S. Neuron (1998) [Pubmed]
  21. Mechanisms of protein import across the mitochondrial outer membrane. Lill, R., Neupert, W. Trends Cell Biol. (1996) [Pubmed]
  22. Structural (betaalpha)8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase. Casals, N., Gómez-Puertas, P., Pié, J., Mir, C., Roca, R., Puisac, B., Aledo, R., Clotet, J., Menao, S., Serra, D., Asins, G., Till, J., Elias-Jones, A.C., Cresto, J.C., Chamoles, N.A., Abdenur, J.E., Mayatepek, E., Besley, G., Valencia, A., Hegardt, F.G. J. Biol. Chem. (2003) [Pubmed]
  23. Human TIM-1 Associates with the TCR Complex and Up-Regulates T Cell Activation Signals. Binné, L.L., Scott, M.L., Rennert, P.D. J. Immunol. (2007) [Pubmed]
  24. Human Tim/Timeless-interacting Protein, Tipin, Is Required for Efficient Progression of S Phase and DNA Replication Checkpoint. Yoshizawa-Sugata, N., Masai, H. J. Biol. Chem. (2007) [Pubmed]
  25. The mitochondrial import machinery for preproteins. Rehling, P., Wiedemann, N., Pfanner, N., Truscott, K.N. Crit. Rev. Biochem. Mol. Biol. (2001) [Pubmed]
  26. Prevention of the ischemia-induced decrease in mitochondrial Tom20 content by ischemic preconditioning. Boengler, K., Gres, P., Cabestrero, A., Ruiz-Meana, M., Garcia-Dorado, D., Heusch, G., Schulz, R. J. Mol. Cell. Cardiol. (2006) [Pubmed]
  27. The exon 4 variations of Tim-1 gene are associated with rheumatoid arthritis in a Korean population. Chae, S.C., Song, J.H., Shim, S.C., Yoon, K.S., Chung, H.T. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  28. TIM-1 regulates macrophage cytokine production and B7 family member expression. Hein, R.M., Woods, M.L. Immunol. Lett. (2007) [Pubmed]
  29. The polymorphisms of Th1 cell surface gene Tim-3 are associated in a Korean population with rheumatoid arthritis. Chae, S.C., Park, Y.R., Shim, S.C., Yoon, K.S., Chung, H.T. Immunol. Lett. (2004) [Pubmed]
  30. Crystal structures of two bacterial 3-hydroxy-3-methylglutaryl-CoA lyases suggest a common catalytic mechanism among a family of TIM barrel metalloenzymes cleaving carbon-carbon bonds. Forouhar, F., Hussain, M., Farid, R., Benach, J., Abashidze, M., Edstrom, W.C., Vorobiev, S.M., Xiao, R., Acton, T.B., Fu, Z., Kim, J.J., Miziorko, H.M., Montelione, G.T., Hunt, J.F. J. Biol. Chem. (2006) [Pubmed]
  31. Inactivation of triosephosphate isomerase from Trypanosoma cruzi by an agent that perturbs its dimer interface. Téllez-Valencia, A., Olivares-Illana, V., Hernández-Santoyo, A., Pérez-Montfort, R., Costas, M., Rodríguez-Romero, A., López-Calahorra, F., Tuena De Gómez-Puyou, M., Gómez-Puyou, A. J. Mol. Biol. (2004) [Pubmed]
  32. Differences in the intersubunit contacts in triosephosphate isomerase from two closely related pathogenic trypanosomes. Maldonado, E., Soriano-García, M., Moreno, A., Cabrera, N., Garza-Ramos, G., de Gómez-Puyou, M., Gómez-Puyou, A., Perez-Montfort, R. J. Mol. Biol. (1998) [Pubmed]
  33. Epitope-Dependent Effect of Anti-Murine TIM-1 Monoclonal Antibodies on T Cell Activity and Lung Immune Responses. Sizing, I.D., Bailly, V., McCoon, P., Chang, W., Rao, S., Pablo, L., Rennard, R., Walsh, M., Li, Z., Zafari, M., Dobles, M., Tarilonte, L., Miklasz, S., Majeau, G., Godbout, K., Scott, M.L., Rennert, P.D. J. Immunol. (2007) [Pubmed]
  34. Exploring the environmental preference of weak interactions in (alpha/beta)8 barrel proteins. Chakkaravarthi, S., Babu, M.M., Gromiha, M.M., Jayaraman, G., Sethumadhavan, R. Proteins (2006) [Pubmed]
  35. Triose phosphate isomerase, a novel enzyme-crystallin, and tau-crystallin in crocodile cornea. High accumulation of both proteins during late embryonic development. Kathiresan, T., Krishnan, K., Krishnakumar, V., Agrawal, R., Anand, A., Muralidhar, D., Mishra, A.K., Dhople, V.M., Aggrawal, R.K., Sharma, Y. FEBS J. (2006) [Pubmed]
  36. JETLAG resets the Drosophila circadian clock by promoting light-induced degradation of TIMELESS. Koh, K., Zheng, X., Sehgal, A. Science (2006) [Pubmed]
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