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Gene Review

TIM44  -  Tim44p

Saccharomyces cerevisiae S288c

Synonyms: ISP45, Inner membrane import site protein 45, MIM44, MPI1, Membrane import machinery protein MIM44, ...
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Disease relevance of TIM44

  • To understand how this motor is anchored to the inner membrane, we have overexpressed Tim44 in Escherichia coli and studied the properties of the pure protein and its interaction with model lipid membranes [1].
  • We investigated the role of Tim44 in the biogenesis of the authentic mitochondrial protein Yfh1p, the yeast homolog of mammalian frataxin, which was recently implicated in Friedreich ataxia [2].

High impact information on TIM44

  • Precursor proteins carrying amino-terminal targeting signals are translocated into the matrix by the integral inner membrane proteins Tim23 and Tim17 in cooperation with Tim44 and mitochondrial Hsp70 [3].
  • Tim44 is associated with this channel at the matrix side, and Tim44 recruits mitochondrial Hsp70 and its co-chaperone Mgel, which drive protein translocation into the matrix using ATP as an energy source [4].
  • This molecular chaperone of the mitochondrial matrix is recruited to the protein import machinery by MIM44, a component associated with the inner membrane of the mitochondria [5].
  • MIM44 and mt-Hsp 70 interact in a sequential manner with incoming segments of unfolded preproteins and thereby facilitate stepwise vectorial translocation of proteins across the mitochondrial membranes [5].
  • The novel J-protein (encoded by PAM18/YLR008c/TIM14) is required for the interaction of mtHsp70 with Tim44 and protein translocation into the matrix [6].

Biological context of TIM44

  • The essential gene TIM44 encodes a subunit of the inner mitochondrial membrane preprotein translocase that forms a complex with the matrix heat-shock protein Hsp70 [7].
  • The membrane potential (delta psi)- and the mtHsp70/MIM44-dependent import machinery cooperate in the transfer of the presequence across the inner membrane [8].
  • Hydrolysis of ATP by mt-Hsp70 occurs in complex with Tim44 [9].
  • MPI1 encodes a hydrophilic 48.8 kDa protein that is essential for cell viability [10].
  • One mutant mtHsp70 (Ssc1-2p) efficiently bound preproteins, but did not show a detectable complex formation with Tim44; the mitochondria imported loosely folded preproteins with wild-type kinetics, yet were impaired in unfolding of preproteins [11].

Anatomical context of TIM44

  • Upon depletion of Tim44, mitochondria also lost their ability to import proteins but maintained normal numbers of import channels [12].
  • Preprotein import into mitochondria is mediated by translocases located in the outer and inner membranes (Tom and Tim) and a matrix Hsp70-Tim44 driving system [13].
  • The essential yeast gene MPI1 encodes a mitochondrial membrane protein that is possibly involved in protein import into the organelle (A. C. Maarse, J. Blom, L. A. Grivell, and M. Meijer, EMBO J. 11:3619-3628, 1992) [14].

Associations of TIM44 with chemical compounds


Physical interactions of TIM44

  • We conclude that Mge1p exerts an essential function in import and folding of proteins by controlling the nucleotide-dependent binding of mt-Hsp70 to substrate proteins and the association of mt-Hsp70 with MIM44 [18].

Other interactions of TIM44

  • A screening for yeast mutants impaired in mitochondrial protein import led to the identification of two genes (MPII and MPI2) encoding the essential components MIM44 and MIM17 of the inner membrane import machinery [19].
  • Outer and inner mitochondrial membrane receptors shown to participate in translocation of mitochondrial pre-proteins (MOM19 and MPI1/MIM44, respectively) are also important for import of the tRNA, in vitro as well as in vivo [20].
  • Three essential subunits of the motor are known: mitochondrial Hsp70 (mtHsp70); the peripheral membrane protein Tim44; and the nucleotide exchange factor Mge1 [6].
  • However, even under these conditions, no interaction of Ssq1 with the two other mitochondrial Hsp70-cochaperones, Tim44 and Mdj1, was observed [21].
  • Mitochondrial protein import: recognition of internal import signals of BCS1 by the TOM complex [22].

Analytical, diagnostic and therapeutic context of TIM44

  • Limited proteolysis and analytical ultracentrifugation indicate that Tim44 is an elongated monomer with a stably folded C-terminal domain [1].


  1. Domain structure and lipid interaction of recombinant yeast Tim44. Weiss, C., Oppliger, W., Vergères, G., Demel, R., Jenö, P., Horst, M., de Kruijff, B., Schatz, G., Azem, A. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  2. Biogenesis of the yeast frataxin homolog Yfh1p. Tim44-dependent transfer to mtHsp70 facilitates folding of newly imported proteins in mitochondria. Geissler, A., Krimmer, T., Schönfisch, B., Meijer, M., Rassow, J. Eur. J. Biochem. (2000) [Pubmed]
  3. Carrier protein import into mitochondria mediated by the intermembrane proteins Tim10/Mrs11 and Tim12/Mrs5. Sirrenberg, C., Endres, M., Fölsch, H., Stuart, R.A., Neupert, W., Brunner, M. Nature (1998) [Pubmed]
  4. Import of carrier proteins into the mitochondrial inner membrane mediated by Tim22. Sirrenberg, C., Bauer, M.F., Guiard, B., Neupert, W., Brunner, M. Nature (1996) [Pubmed]
  5. Mitochondrial Hsp70/MIM44 complex facilitates protein import. Schneider, H.C., Berthold, J., Bauer, M.F., Dietmeier, K., Guiard, B., Brunner, M., Neupert, W. Nature (1994) [Pubmed]
  6. A J-protein is an essential subunit of the presequence translocase-associated protein import motor of mitochondria. Truscott, K.N., Voos, W., Frazier, A.E., Lind, M., Li, Y., Geissler, A., Dudek, J., Müller, H., Sickmann, A., Meyer, H.E., Meisinger, C., Guiard, B., Rehling, P., Pfanner, N. J. Cell Biol. (2003) [Pubmed]
  7. Separation of structural and dynamic functions of the mitochondrial translocase: Tim44 is crucial for the inner membrane import sites in translocation of tightly folded domains, but not of loosely folded preproteins. Bömer, U., Maarse, A.C., Martin, F., Geissler, A., Merlin, A., Schönfisch, B., Meijer, M., Pfanner, N., Rassow, J. EMBO J. (1998) [Pubmed]
  8. The delta psi- and Hsp70/MIM44-dependent reaction cycle driving early steps of protein import into mitochondria. Ungermann, C., Guiard, B., Neupert, W., Cyr, D.M. EMBO J. (1996) [Pubmed]
  9. The nucleotide exchange factor MGE exerts a key function in the ATP-dependent cycle of mt-Hsp70-Tim44 interaction driving mitochondrial protein import. Schneider, H.C., Westermann, B., Neupert, W., Brunner, M. EMBO J. (1996) [Pubmed]
  10. MPI1, an essential gene encoding a mitochondrial membrane protein, is possibly involved in protein import into yeast mitochondria. Maarse, A.C., Blom, J., Grivell, L.A., Meijer, M. EMBO J. (1992) [Pubmed]
  11. Differential requirement for the mitochondrial Hsp70-Tim44 complex in unfolding and translocation of preproteins. Voos, W., von Ahsen, O., Müller, H., Guiard, B., Rassow, J., Pfanner, N. EMBO J. (1996) [Pubmed]
  12. Modular structure of the TIM23 preprotein translocase of mitochondria. Milisav, I., Moro, F., Neupert, W., Brunner, M. J. Biol. Chem. (2001) [Pubmed]
  13. The Tim core complex defines the number of mitochondrial translocation contact sites and can hold arrested preproteins in the absence of matrix Hsp70-Tim44. Dekker, P.J., Martin, F., Maarse, A.C., Bömer, U., Müller, H., Guiard, B., Meijer, M., Rassow, J., Pfanner, N. EMBO J. (1997) [Pubmed]
  14. The essential yeast protein MIM44 (encoded by MPI1) is involved in an early step of preprotein translocation across the mitochondrial inner membrane. Blom, J., Kübrich, M., Rassow, J., Voos, W., Dekker, P.J., Maarse, A.C., Meijer, M., Pfanner, N. Mol. Cell. Biol. (1993) [Pubmed]
  15. Protein import into yeast mitochondria: the inner membrane import site protein ISP45 is the MPI1 gene product. Horst, M., Jenö, P., Kronidou, N.G., Bolliger, L., Oppliger, W., Scherer, P., Manning-Krieg, U., Jascur, T., Schatz, G. EMBO J. (1993) [Pubmed]
  16. Dynamic interaction between Isp45 and mitochondrial hsp70 in the protein import system of the yeast mitochondrial inner membrane. Kronidou, N.G., Oppliger, W., Bolliger, L., Hannavy, K., Glick, B.S., Schatz, G., Horst, M. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  17. Probing the membrane topology of a subunit of the mitochondrial protein translocase, Tim44, with biotin maleimide. Pavlov, P.F., Glaser, E. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  18. The role of the GrpE homologue, Mge1p, in mediating protein import and protein folding in mitochondria. Westermann, B., Prip-Buus, C., Neupert, W., Schwarz, E. EMBO J. (1995) [Pubmed]
  19. Identification of MIM23, a putative component of the protein import machinery of the mitochondrial inner membrane. Dekker, P.J., Keil, P., Rassow, J., Maarse, A.C., Pfanner, N., Meijer, M. FEBS Lett. (1993) [Pubmed]
  20. An intact protein translocating machinery is required for mitochondrial import of a yeast cytoplasmic tRNA. Tarassov, I., Entelis, N., Martin, R.P. J. Mol. Biol. (1995) [Pubmed]
  21. The two mitochondrial heat shock proteins 70, Ssc1 and Ssq1, compete for the cochaperone Mge1. Schmidt, S., Strub, A., Röttgers, K., Zufall, N., Voos, W. J. Mol. Biol. (2001) [Pubmed]
  22. Mitochondrial protein import: recognition of internal import signals of BCS1 by the TOM complex. Stan, T., Brix, J., Schneider-Mergener, J., Pfanner, N., Neupert, W., Rapaport, D. Mol. Cell. Biol. (2003) [Pubmed]
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