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Kostas Tokatlidis

Kostas Tokatlidis

IMBB Group Leader (Full Professor, Univ. of Crete)
Email address
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Phone
+30-2810-391136
Fax
+30-2810-391101, 391258
Lab web page

Our main interest is the biogenesis of mitochondria and their relevance in health and disease. About 30 % of the human proteome are proteins targeted to a site of action distant to their synthesis, highlighting the importance of correct intracellular targeting for cell function. Mitochondria are crucial for energy metabolism and physiology but involved in medical conditions (neurodegeneration, cancer) and apoptosis. Their biogenesis relies on protein import as more than 98% of mitochondrial proteins are targeted from the cytosol. We focus on proteins of the mitochondrial intermembrane space that are involved in respiration, metal homeostasis and apoptosis and undergo oxidative folding by adopting intramolecular disulfide bridges. We study this machinery, its molecular mechanism and structural basis and its relevance for cell physiology. We combine molecular/cell biology approaches (mutagenesis, yeast genetics, confocal microscopy, cell fractionation), biochemical characterisation (protein purification, chemical crosslinking, redox assays, reconstitution and import assays), proteomics approaches (bottom-up and top-down) and biophysical analyses (light scattering, fluorescence, circular dichroism, calorimetry, surface plasmon resonance). Our ongoing efforts build on our contributions to key concepts, components, targeting signals and mechanistic features and develop to determine the relevance of the mitochondrial oxidative folding and signalling for cell physiology.

Banci L., Bertini I., Calderone, V., Cefaro C., Ciofi-Baffoni S., Gallo A., Kallergi, E., Lionaki, E., Pozidis, C. Tokatlidis K. (2011) Molecular recognition and substrate mimicry drive the electron transfer process between MIA40 and ALR. Proc Natl Acad. Sci USA 108: 4811-4816.

Banci L., Bertini I., Cefaro C., Cenacchi, L., Ciofi-Baffoni S., Felli, I.C., Gallo A., Gonnelli, L., Luchinat, E., Sideris D.P. Tokatlidis K. (2010) A molecular chaperone function of Mia40 triggers consecutive induced folding steps of the substrate in mitochondrial protein import. Proc Natl Acad. Sci USA 107: 20190-20195.

Banci L., Bertini I., Cefaro C., Ciofi-Baffoni S., Gallo A., Martinelli M., Sideris DP, Katrakili N. Tokatlidis K. (2009) MIA40 is an oxidoreductase catalyzing oxidative protein folding in mitochondria. Nature Structural and Molecular Biology 16: 198-206.

Sideris, D.P., Petrakis, N., Katrakili, N., Mikropoulou, D., Gallo, A., Ciofi-Baffoni, S., Banci, L., Bertini, I., Tokatlidis, K. (2009) A novel targeting signal primes precursors for correct cysteine docking onto Mia40 in the mitochondrial intermembrane space. J. Cell Biol. 187: 1007-1022.

Tokatlidis, K., Junne, T., Moes, S., Schatz, G., Glick, B.S. Kronidou, N. (1996) Translocation arrest of an intramitochondrial sorting signal next to Tim11p, a novel protein of the inner membrane import site. Nature 384: 585-588.

2016

Kalef-Ezra E, Kotzamani D, Zaganas I, Katrakili N, Plaitakis A, Tokatlidis K. (2016) ., Import of a major mitochondrial enzyme depends on synergy between two distinct helices of its presequence. Biochem J. 2016 Sep 15;473(18):2813-29. PMID:27422783
[abstract]

2014

Kallergi E, Kalef-Ezra E, Karagouni-Dalakoura K, Tokatlidis K. (2014) Common Players in Mitochondria Biogenesis and Neuronal Protection Against Stress-Induced Apoptosis. Neurochem Res. PMID:24005821
[abstract]

2013

Chatzi A, Sideris DP, Katrakili N, Pozidis C, Tokatlidis K. (2013) Biogenesis of yeast Mia40: Uncoupling folding from import and atypical recognition features. FEBS J. doi: 10.1111/febs.12482
[abstract]

Chatzi A, Tokatlidis K. (2013) The mitochondrial intermembrane space: A hub for oxidative folding linked to protein biogenesis. Antioxid Redox Signal. 19(1):54-62
[abstract]

2012

Banci L, Bertini I, Cefaro C, Ciofi-Baffoni S, Gajda K, Felli IC, Gallo A, Pavelkova A, Kallergi E, Andreadaki M, Katrakili N, Pozidis C and Tokatlidis K. (2012) An intrinsically disordered domain has a dual function coupled to compartment-dependent redox control. J Mol Biol. (in press, DOI: 10.1016/j.jmb.2012.11.032)

Banci L., Bertini I., Calderone, V., Cefaro C., Ciofi-Baffoni S., Gallo A. and Tokatlidis K. (2012) An electron transfer path through an extended disulfide relay system: the case of the redox protein ALR. J Am Chem Soc. 134(3):1442-5
[abstract]

Chatzi A. and Tokatlidis K (2012) Redox-dependent protein biogenesis and folding in the mitochondrial intermembrane space (submitted)

Kallergi E, Andreadaki M, Kritsiligkou P, Katrakili N, Pozidis C, Tokatlidis K, Banci L, Bertini I, Cefaro C, Ciofi-Baffoni S, Gajda K, Peruzzini R (2012) Targeting and maturation of Erv1/ ALR in the mitochondrial intermembrane space. ACS Chem. Biol. [Epub ahead of print]
[abstract]

Chatzi A, Sideris D.P, Katrakili N, Pozidis C and Tokatlidis K (2012) Uncoupling folding from import in the oxidative protein folding pathway in mitochondria. (submitted)

2011

Banci L, Bertini I, Ciofi-Baffoni, S., Boscaro, F, Chatzi, A, Mikolajczyk, M, Tokatlidis, K. Winkelmann, J. (2011) Anamorsin is a [2Fe-2S] cluster-containing substrate of the Mia40-dependent mitochondrial protein trapping machinery. Chemistry& Biology 18(6):794-804
[abstract]

Banci L, Bertini I, Calderone V, Cefaro C, Ciofi-Baffoni S, Gallo A, Kallergi E, Lionaki E, Pozidis C, Tokatlidis K (2011) Molecular recognition and substrate mimicry drive the electron-transfer process between MIA40 and ALR. Proc Natl Acad Sci U S A 108(12):4811-4816
[abstract]

2010

Banci L, Bertini I, Cefaro C, Cenacchi L, Ciofi-Baffoni S, Felli IC, Gallo A, Gonnelli L, Luchinat E, Sideris D. and Tokatlidis K. (2010)

Molecular chaperone function of Mia40 triggers consecutive induced folding steps of the substrate in mitochondrial protein import

Proc Natl Acad Sci U S A 107(47):20190-20195

[abstract]

Sideris, D. P. and Tokatlidis, K. (2010) Trapping oxidative folding intermediates during translocation to the intermembrane space of mitochondria: In Vivo and In Vitro Studies Methods Mol Biol. 619, 411-423

[abstract]

Sideris, D. P and Tokatlidis, K. (2010) Oxidative protein folding in the mitochondrial intermembrane space

Antioxid Redox Signal. 13(8):1189-1204

[abstract]

Lionaki E., Aivaliotis M., Pozidis C. and Tokatlidis K. (2010) The N-terminal shuttle domain of Erv1 determines the affinity for Mia40 and mediates electron transfer to the catalytic Erv1 core in yeast mitochondria

Antiox. Redox Signal. 13(9):1327-1339

[abstract]

2009

Sideris, D.P., Petrakis, N., Katrakili, N., Mikropoulou, D., Gallo, A., Ciofi-Baffoni S., Banci L., Bertini I., and Tokatlidis K. (2009) A novel intermembrane space targeting signal docks cysteines onto Mia40 during mitochondrial oxidative folding

J. Cell Biol. 187(7), 1007-1022; Epub 2009 Dec 21

[abstract][PDF]

Petrakis, N., Alcock, F.H. and Tokatlidis, K. (2009) Mitochondrial ATP-independent chaperones IUBMB life 61(9), 909-914

Banci L., Bertini I., Ciofi-Baffoni S. and Tokatlidis K.(2009) The coiled coil-helix-coiled coil-helix proteins may be redox proteins

FEBS Lett. 583(11), 1699-1702

[abstract][PDF]

Banci L., Bertini I., Cefaro C., Ciofi-Baffoni S., Gallo A., Martinelli M., Sideris DP, Katrakili N. and Tokatlidis K. (2009) MIA40 is an oxidoreductase catalyzing oxidative protein folding in mitochondria, Nature Structural and Molecular Biology 16(2), 198-206 (2009)

[abstract][PDF]

2008

Lionaki. E., de Marcos Lousa, C., Baud, C., Vougioukalaki, M., Panayotou, G., and Tokatlidis, K. (2008) The essential function of Tim12 in vivo is ensured by the assembly interactions of its C-terminal domain  J. Biol. Chem. 283(23), 15747-15753
[abstract][PDF]

Grossmann, J.G., Callaghan, A.J., Marcaida, M.J., Luisi, B.F., Alcock, F.H. and Tokatlidis, K. (2008) Complementing structural information of modular proteins with small angle neutron scattering and contrast variation Eur. J. Biophys. 37(5), 603-611

[abstract][PDF]

Roussakis, E., Voutsadaki, E., Pinakoulaki, E., Sideris, D.P., Tokatlidis, K. and Katerinopoulos, H.E. (2008) ICPBCZin: A red emitting ratiometric fluorescent indicator with nanomolar affinity for Zn2+ ions. Cell Calcium 44(3), 270-275

[abstract][PDF]

Alcock, F.H., Grossmann, J.G., Gentle, I.E., Likic, V.A., Lithgow, T. and Tokatlidis, K. (2008) Conserved Substrate-binding by Chaperones in the Bacterial Periplasm and the Mitochondrial Intermembrane Space, Biochem. J. 409(2), 377-387

[abstract][PDF]

2007

Sideris, D.P. and Tokatlidis, K. (2007) Oxidative folding of small Tims mediated by site-specific docking onto Mia40 in the mitochondrial intermembrane space. Mol. Microbiol. 65(5),1360-1373

[abstract][PDF]

Vergnolle, M.A.S., Alcock, F.H., Petrakis, N. and Tokatlidis  K. (2007) Mutation of conserved charged residues in mitochondrial TIM10 subunits precludes TIM10 complex assembly, but does not abolish growth of yeast cells, J. Mol. Biol. 371(5), 1315-1324
[abstract][PDF]

Baud, C., de Marcos-Lousa, C. and Tokatlidis, K. (2007) Molecular interactions of the mitochondrial Tim12 translocase subunit Prot. Pept. Lett. 14(6), 597-600

[abstract]

Gentle I.E., Perry, A.J., Alcock, F.H., Likic, V.A., Dolezal, P., Ng, E.T., Purcell, A.W., McConnville, M., Naderer, T., Chanez, A.L., Charriere, F., Aschinger, C., Schneider, A., Tokatlidis, K. and Lithgow T. (2007) Conserved motifs reveal details of ancestry and structure in the small TIM chaperones of the mitochondrial intermembrane space Mol. Biol. Evol. 24(5), 1149-1160.

[abstract][PDF]

2006

de Marcos-Lousa C., Sideris, D.P. and Tokatlidis, K. (2006) Translocation of mitochondrial inner-membrane proteins: Conformation matters Trends in Biochemical Sciences 31(5), 259-267.
[abstract][PDF]

2005
Tokatlidis, K. (2005) A disulfide relay system in mitochondria
Cell, 121, 965-967.
[abstract][PDF]

Allen, S., Balabanidou, V., Sideris, D.P., Lisowsky, T. and Tokatlidis, K., (2005) Erv1 mediates the Mia40-dependent protein import pathway and provides a functional link to the respiratory chain by shuttling electrons to cytochrome c
J. Mol. Biol. 353(5), 937-944.
[abstract][PDF]
JMB cover Nov11- 2005

Vergnolle, M.A.S, Baud C., Golovanov, A.P., Alcock, F., Luciano, P., Lian. L.Y., and Tokatlidis, K. (2005) Distinct domains of small Tims involved in subunit interaction and substrate recognition
J. Mol. Biol. 351, 839-849.
[abstract][PDF]

Vergnolle MA, Sawney H, Junne T, Dolfini L, Tokatlidis K (2005) A cryptic matrix targeting signal of the yeast ADP/ATP carrier normally inserted by the TIM22 complex is recognised by the TIM23 machinery
Biochem J.384, 1-8.
[abstract][PDF]

2004
Lu, H., Allen, S., Wardleworth, L., Savory, P. and Tokatlidis, K. (2004) Functional TIM10 chaperone assembly is redox-regulated in vivo
J. Biol. Chem. 279,18952-18958.
[abstract][PDF]

Lu, H., Golovanov, A.P., Alcock, F., Grossmann, J.G., Allen, S., Lian, L.-Y. and Tokatlidis, K. (2004) The structural basis of the TIM10 chaperone assembly
J. Biol. Chem 279,18959-18966.
[abstract][PDF]

2003
Dyall, S.D., Agius, S.C., de Marcos Lousa, C., Trezeguet, V. and Tokatlidis, K. (2003) The dynamic dimerisation of yeast ADP/ATP carrier in the inner membrane is affected by conserved cysteine residues
J. Biol. Chem. 278, 26757-26764
[abstract][PDF]

Allen, S., Lu, H., Thornton, D. and Tokatlidis, K. (2003) Juxtaposition of the two distal "CX3C" motifs via intrachain disulfide bonding is essential for the folding of Tim10
J. Biol. Chem. 278, 38505-38513
[abstract][PDF]

Tokatlidis, K. and Grossmann, J.G (2003) Structural insights into a protein escort system.
Daresbury Laboratory Annual Report 2003, 26-27
[PDF]

2002
Vial S., Lu. H., Allen S., Savory P., Thornton D., Sheehan J. and Tokatlidis K. (2002) Assembly of Tim9 and Tim10 into a functional chaperone
J. Biol. Chem., 277(39), 36100-36108
[abstract][PDF]

Minczuk, M. Piwowarski, J., Papworth, M., Awiszus, K., Schalinski, S., Dziembowski, A., Dmochowska, A., Bartnik, E., Tokatlidis, K., Stepien, P. and Borowski, P. (2002) Localisation of the human hSuv3p helicase in the mitochondrial matrix and its preferential unwinding of ds DNA
Nucl. Acids Res. 30(23), 5074-5086
[abstract][PDF]

2001
Luciano, P., Vial S., Vergnolle M., Dyall S., Robinson D. and Tokatlidis K. (2001) Functional reconstitution of the yeast ADP/ATP carrier import mediated by the TIM10 complex
EMBO J. 20(15), 4099-4106
[abstract][PDF]

2000
Tokatlidis K. (2000) "Directing of proteins to mitochondria by fusion to mitochondrial targeting signals". Methods in Enzymology vol. 327, Application of chimeric genes and Hybrid proteins, Ed. Thorner, J., Emr, S.D. and Abelson, J.N. 305-317
[abstract][PDF]

Tokatlidis, K., Vial, S., Luciano, P., Vergnolle, M., and Cl?mence, S. Membrane protein import in yeast mitochondria, (2000)
Biochem. Soc. Transactions, 28, 495-499
[abstract][PDF]

1999
Tokatlidis, K. and Schatz, G. (1999) Biogenesis of mitochondrial inner membrane proteins
J. Biol. Chem 274, 35285-35288
[abstract][PDF]

1998
Koehler, C.M., Merchant, S., Oppliger. W, Schmid, K., Jarosch, E., Dolfini, L., Junne, T., Schatz, G. and Tokatlidis, K. (1998) Tim9p, an essential partner subunit of Tim10p for the import of mitochondrial carrier proteins
EMBO J.17, 6477-6486.
[abstract][PDF]

Luciano, P., Tokatlidis, K., Chambre, I., Germanique, J.-C. and Geli, V. (1998) The mitochondrial processing peptidase behaves as a zinc-metallopeptidase
J. Mol. Biol. 280, 193-199
[abstract][PDF]

Koehler, C.M., Jarosch, E., Tokatlidis, K., Schmid, K., Schweyen, R.J. and Schatz, G. (1998) Import of mitochondrial carriers mediated by essential proteins of the intermembrane space Science 279, 369-373.
[abstract][PDF]

1997
Haucke, V., Santos-Ocana, C., Henlinger, A., Tokatlidis, K., Pfanner, N. and Schatz, G. (1997) Analysis of the sorting signals directing NADH-cytochrome b5 reductase to two locations within yeast mitochondria.
Mol. Cell Biol. 17, 4024-4032
[abstract][PDF]

1996
Tokatlidis, K., Junne, T., Moes, S., Schatz, G., Glick, B.S. and Kronidou, N. (1996) Translocation arrest of an intramitochondrial sorting signal next to Tim11p, a novel protein of the inner membrane import site.
Nature 384, 585-588
[abstract]

1995
Tokatlidis, K. Friguet, B., Deville-Bonne, D., Baleux, F., Fedorov, A.N., Navon, A., Djavadi-Ohaniance, L. and Goldberg, M. (1995) Nascent chains: Folding and chaperone interaction during elongation on ribosomes,
Phil.Trans.R. Soc. Lond. B, 348, 89-95
[abstract]

1993
Tokatlidis, K., Dhurjati, P., and Beguin, P. (1993) Properties conferred onC. thermocellum endoglucanase CelC by grafting the duplicated segment of endoglucanase CelD.
Protein Engineering, 6, 947-952
[abstract]

Tokatlidis, K., Salamitou, S., Fujino, T., B?guin, P., Dhurjati, P., Millet, J. and Aubert,J.-P. (1993) Duplicated segment of Clostridium thermocellum cellulases In Protein Folding: in vivo and in vitro Ed. J. Cleland. American Chemical Society Symposium Series No 526, Washington, D.C.

1992
Salamitou, S., Tokatlidis, K., Beguin, P., and Aubert, J.-P. (1992) Involvement of separate domains of the cellulosomal protein S1 of Clostridium thermocellum in binding to cellulose and in anchoring of catalytic subunits to the cellulosome,
FEBS Lett., 304, 89-92
[abstract]

Beguin, P., Millet, J., Chauvaux, S., Salamitou, S., Tokatlidis, K., Navas, J., Fujino, T., Lemaire, M., Raynaud, O., Daniel, M.-K. and Aubert, J.-P. (1992) Bacterial Cellulases. Biochem. Soc. Transactions, 20, 42-46
[abstract]

1991
Tokatlidis, K., Salamitou, S., Beguin, P., Dhurjati, P., and Aubert, J.-P. (1991) Interaction of the duplicated segment carried by Clostridium thermocellum cellulases with cellulosome components
FEBS Lett., 291,185-188
[abstract]

Tokatlidis, K., Dhurjati, P., Millet, J., Beguin, P. and Aubert, J.-P. (1991) High activity of inclusion bodies formed in Escherichia coli overproducing Clostridium thermocellum endoglucanase D
FEBS Lett., 282, 205-208
[abstract]

 

 

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