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Tim Clausen

Our group employs an integrative Structural Biology approach to study complex proteases and chaperones that function as safeguards in the cell, preventing other proteins from undergoing dangerous interactions. By addressing mechanistic details of the protein-quality-control machinery, we aim to develop strategies against misbehaving proteins connected with neurodegenerative diseases, inclusion body myopathies, cancer and ageing. Moreover, differences in the protein folding and protein degradation pathways between bacterial pathogens and their hosts will guide the development of novel antibiotics.

Publications

2018

Hellerschmied, D., Roessler, M., Lehner, A., Gazda, L., Stejskal, K., Imre, R., Mechtler, K., Dammermann, A., Clausen, T. (2018) UFD-2 is an adaptor-assisted E3 ligase targeting unfolded proteins. Nat Commun. 9(1):484

2017

Ouyang, M., Li, X., Zhao, S., Pu, H., Shen, J., Adam, Z., Clausen, T., Zhang, L. (2017) The crystal structure of Deg9 reveals a novel octameric-type HtrA protease. Nat Plants. 3(12):973-982

2016

Gallego, LD., Ghodgaonkar Steger, M., Polyansky, AA., Schubert, T., Zagrovic, B., Zheng, N., Clausen, T., Herzog, F., Köhler, A. (2016) Structural mechanism for the recognition and ubiquitination of a single nucleosome residue by Rad6-Bre1. Proc Natl Acad Sci U S A. 113(38):10553-8
Heuck, A., Schitter-Sollner, S., Suskiewicz, MJ., Kurzbauer, R., Kley, J., Schleiffer, A., Rombaut, P., Herzog, F., Clausen, T. (2016) Structural basis for the disaggregase activity and regulation of Hsp104. Elife. 5
Suskiewicz, MJ., Clausen, T. (2016) Chemical Biology Interrogates Protein Arginine Phosphorylation. Cell Chem Biol. 23(8):888-90
Trentini, DB., Suskiewicz, MJ., Heuck, A., Kurzbauer, R., Deszcz, L., Mechtler, K., Clausen, T. (2016) Arginine phosphorylation marks proteins for degradation by a Clp protease. Nature. 539(7627):48-53

2015

Poepsel, S., Sprengel, A., Sacca, B., Kaschani, F., Kaiser, M., Gatsogiannis, C., Raunser, S., Clausen, T., Ehrmann, M. (2015) Determinants of amyloid fibril degradation by the PDZ protease HTRA1. Nat Chem Biol. 11(11):862-9
Schneider, M., Hellerschmied, D., Schubert, T., Amlacher, S., Vinayachandran, V., Reja, R., Pugh, BF., Clausen, T., Köhler, A. (2015) The Nuclear Pore-Associated TREX-2 Complex Employs Mediator to Regulate Gene Expression. Cell. 162(5):1016-28

2014

Dikfidan, A., Loll, B., Zeymer, C., Magler, I., Clausen, T., Meinhart, A. (2014) RNA specificity and regulation of catalysis in the eukaryotic polynucleotide kinase Clp1. Mol Cell. 54(6):975-86
Hellerschmied, D., Clausen, T. (2014) Myosin chaperones. Curr Opin Struct Biol. 25:9-15
Karaca, E., Weitzer, S., Pehlivan, D., Shiraishi, H., Gogakos, T., Hanada, T., Jhangiani, SN., Wiszniewski, W., Withers, M., Campbell, IM., Erdin, S., Isikay, S., Franco, LM., Gonzaga-Jauregui, C., Gambin, T., Gelowani, V., Hunter, JV., Yesil, G., Koparir, E., Yilmaz, S., Brown, M., Briskin, D., Hafner, M., Morozov, P., Farazi, TA., Bernreuther, C., Glatzel, M., Trattnig, S., Friske, J., Kronnerwetter, C., Bainbridge, MN., Gezdirici, A., Seven, M., Muzny, DM., Boerwinkle, E., Ozen, M., Clausen, T., Tuschl, T., Yuksel, A., Hess, A., Gibbs, RA., Martinez, J., Penninger, JM., Lupski, JR. (2014) Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function. Cell. 157(3):636-50
Norell, D., Heuck, A., Tran-Thi, TA., Götzke, H., Jacob-Dubuisson, F., Clausen, T., Daley, DO., Braun, V., Müller, M., Fan, E. (2014) Versatile in vitro system to study translocation and functional integration of bacterial outer membrane proteins. Nat Commun. 5:5396
Schmidt, A., Trentini, DB., Spiess, S., Fuhrmann, J., Ammerer, G., Mechtler, K., Clausen, T. (2014) Quantitative phosphoproteomics reveals the role of protein arginine phosphorylation in the bacterial stress response. Mol Cell Proteomics. 13(2):537-50
Trentini, DB., Fuhrmann, J., Mechtler, K., Clausen, T. (2014) Chasing Phosphoarginine Proteins: Development of a Selective Enrichment Method Using a Phosphatase Trap. Mol Cell Proteomics. 13(8):1953-64

2013

Fuhrmann, J., Mierzwa, B., Trentini, DB., Spiess, S., Lehner, A., Charpentier, E., Clausen, T. (2013) Structural basis for recognizing phosphoarginine and evolving residue-specific protein phosphatases in gram-positive bacteria. Cell Rep. 3(6):1832-9
Gazda, L., Pokrzywa, W., Hellerschmied, D., Löwe, T., Forné, I., Mueller-Planitz, F., Hoppe, T., Clausen, T. (2013) The myosin chaperone UNC-45 is organized in tandem modules to support myofilament formation in C. elegans. Cell. 152(1-2):183-95
Malvezzi, F., Litos, G., Schleiffer, A., Heuck, A., Mechtler, K., Clausen, T., Westermann, S. (2013) A structural basis for kinetochore recruitment of the Ndc80 complex via two distinct centromere receptors. EMBO J. 32(3):409-23
Mastny, M., Heuck, A., Kurzbauer, R., Heiduk, A., Boisguerin, P., Volkmer, R., Ehrmann, M., Rodrigues, CD., Rudner, DZ., Clausen, T. (2013) CtpB assembles a gated protease tunnel regulating cell-cell signaling during spore formation in Bacillus subtilis. Cell. 155(3):647-58

2012

Breuss, M., Heng, JI., Poirier, K., Tian, G., Jaglin, XH., Qu, Z., Braun, A., Gstrein, T., Ngo, L., Haas, M., Bahi-Buisson, N., Moutard, ML., Passemard, S., Verloes, A., Gressens, P., Xie, Y., Robson, KJ., Rani, DS., Thangaraj, K., Clausen, T., Chelly, J., Cowan, NJ., Keays, DA. (2012) Mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities. Cell Rep. 2(6):1554-62
Dal Santo, S., Stampfl, H., Krasensky, J., Kempa, S., Gibon, Y., Petutschnig, E., Rozhon, W., Heuck, A., Clausen, T., Jonak, C. (2012) Stress-induced GSK3 regulates the redox stress response by phosphorylating glucose-6-phosphate dehydrogenase in Arabidopsis. Plant Cell. 24(8):3380-92
Malet, H., Canellas, F., Sawa, J., Yan, J., Thalassinos, K., Ehrmann, M., Clausen, T., Saibil, HR. (2012) Newly folded substrates inside the molecular cage of the HtrA chaperone DegQ. Nat Struct Mol Biol. 19(2):152-7
Tennstaedt, A., Pöpsel, S., Truebestein, L., Hauske, P., Brockmann, A., Schmidt, N., Irle, I., Sacca, B., Niemeyer, CM., Brandt, R., Ksiezak-Reding, H., Tirniceriu, AL., Egensperger, R., Baldi, A., Dehmelt, L., Kaiser, M., Huber, R., Clausen, T., Ehrmann, M. (2012) Human high temperature requirement serine protease A1 (HTRA1) degrades tau protein aggregates. J Biol Chem. 287(25):20931-41

2011

Clausen, T., Kaiser, M., Huber, R., Ehrmann, M. (2011) HTRA proteases: regulated proteolysis in protein quality control. Nat Rev Mol Cell Biol. 12(3):152-62
Kley, J., Schmidt, B., Boyanov, B., Stolt-Bergner, PC., Kirk, R., Ehrmann, M., Knopf, RR., Naveh, L., Adam, Z., Clausen, T. (2011) Structural adaptation of the plant protease Deg1 to repair photosystem II during light exposure. Nat Struct Mol Biol. 18(6):728-31
Merdanovic, M., Clausen, T., Kaiser, M., Huber, R., Ehrmann, M. (2011) Protein quality control in the bacterial periplasm. Annu Rev Microbiol. 65:149-68
Sawa, J., Malet, H., Krojer, T., Canellas, F., Ehrmann, M., Clausen, T. (2011) Molecular adaptation of the DegQ protease to exert protein quality control in the bacterial cell envelope. J Biol Chem. 286(35):30680-90
Truebestein, L., Tennstaedt, A., Mönig, T., Krojer, T., Canellas, F., Kaiser, M., Clausen, T., Ehrmann, M. (2011) Substrate-induced remodeling of the active site regulates human HTRA1 activity. Nat Struct Mol Biol. 18(3):386-8

2010

Hasenbein, S., Meltzer, M., Hauske, P., Kaiser, M., Huber, R., Clausen, T., Ehrmann, M. (2010) Conversion of a regulatory into a degradative protease. J Mol Biol. 397(4):957-66
Krojer, T., Sawa, J., Huber, R., Clausen, T. (2010) HtrA proteases have a conserved activation mechanism that can be triggered by distinct molecular cues. Nat Struct Mol Biol. 17(7):844-52
Sawa, J., Heuck, A., Ehrmann, M., Clausen, T. (2010) Molecular transformers in the cell: lessons learned from the DegP protease-chaperone. Curr Opin Struct Biol. 20(2):253-8

2009

Breithaupt, C., Kurzbauer, R., Schaller, F., Stintzi, A., Schaller, A., Huber, R., Macheroux, P., Clausen, T. (2009) Structural basis of substrate specificity of plant 12-oxophytodienoate reductases. J Mol Biol. 392(5):1266-77
Fuhrmann, J., Schmidt, A., Spiess, S., Lehner, A., Turgay, K., Mechtler, K., Charpentier, E., Clausen, T. (2009) McsB is a protein arginine kinase that phosphorylates and inhibits the heat-shock regulator CtsR. Science. 324(5932):1323-7
Hauske, P., Mamant, N., Hasenbein, S., Nickel, S., Ottmann, C., Clausen, T., Ehrmann, M., Kaiser, M. (2009) Peptidic small molecule activators of the stress sensor DegS. Mol Biosyst. 5(9):980-5
Hauske, P., Meltzer, M., Ottmann, C., Krojer, T., Clausen, T., Ehrmann, M., Kaiser, M. (2009) Selectivity profiling of DegP substrates and inhibitors. Bioorg Med Chem. 17(7):2920-4
Holzmann, J., Pichler, P., Madalinski, M., Kurzbauer, R., Mechtler, K. (2009) Stoichiometry determination of the MP1-p14 complex using a novel and cost-efficient method to produce an equimolar mixture of standard peptides. Anal Chem. 81(24):10254-61
Meltzer, M., Hasenbein, S., Mamant, N., Merdanovic, M., Poepsel, S., Hauske, P., Kaiser, M., Huber, R., Krojer, T., Clausen, T., Ehrmann, M. (2009) Structure, function and regulation of the conserved serine proteases DegP and DegS of Escherichia coli. Res Microbiol. 160(9):660-6

2008

Krojer, T., Pangerl, K., Kurt, J., Sawa, J., Stingl, C., Mechtler, K., Huber, R., Ehrmann, M., Clausen, T. (2008) Interplay of PDZ and protease domain of DegP ensures efficient elimination of misfolded proteins. Proc Natl Acad Sci U S A. 105(22):7702-7
Krojer, T., Sawa, J., Schäfer, E., Saibil, HR., Ehrmann, M., Clausen, T. (2008) Structural basis for the regulated protease and chaperone function of DegP. Nature. 453(7197):885-90
Meltzer, M., Hasenbein, S., Hauske, P., Kucz, N., Merdanovic, M., Grau, S., Beil, A., Jones, D., Krojer, T., Clausen, T., Ehrmann, M., Kaiser, M. (2008) Allosteric activation of HtrA protease DegP by stress signals during bacterial protein quality control. Angew Chem Int Ed Engl. 47(7):1332-4

2007

Hasselblatt, H., Kurzbauer, R., Wilken, C., Krojer, T., Sawa, J., Kurt, J., Kirk, R., Hasenbein, S., Ehrmann, M., Clausen, T. (2007) Regulation of the sigmaE stress response by DegS: how the PDZ domain keeps the protease inactive in the resting state and allows integration of different OMP-derived stress signals upon folding stress. Genes Dev. 21(20):2659-70

2006

Breithaupt, C., Kurzbauer, R., Lilie, H., Schaller, A., Strassner, J., Huber, R., Macheroux, P., Clausen, T. (2006) Crystal structure of 12-oxophytodienoate reductase 3 from tomato: self-inhibition by dimerization. Proc Natl Acad Sci U S A. 103(39):14337-42
Grau, S., Richards, PJ., Kerr, B., Hughes, C., Caterson, B., Williams, AS., Junker, U., Jones, SA., Clausen, T., Ehrmann, M. (2006) The role of human HtrA1 in arthritic disease. J Biol Chem. 281(10):6124-9

2005

Grau, S., Baldi, A., Bussani, R., Tian, X., Stefanescu, R., Przybylski, M., Richards, P., Jones, SA., Shridhar, V., Clausen, T., Ehrmann, M. (2005) Implications of the serine protease HtrA1 in amyloid precursor protein processing. Proc Natl Acad Sci U S A. 102(17):6021-6
Groll, M., Bochtler, M., Brandstetter, H., Clausen, T., Huber, R. (2005) Molecular machines for protein degradation. Chembiochem. 6(2):222-56
Kitzing, K., Fitzpatrick, TB., Wilken, C., Sawa, J., Bourenkov, GP., Macheroux, P., Clausen, T. (2005) The 1.3 A crystal structure of the flavoprotein YqjM reveals a novel class of Old Yellow Enzymes. J Biol Chem. 280(30):27904-13
Vietor, I., Kurzbauer, R., Brosch, G., Huber, LA. (2005) TIS7 regulation of the beta-catenin/Tcf-4 target gene osteopontin (OPN) is histone deacetylase-dependent. J Biol Chem. 280(48):39795-801

2004

Ehrmann, M., Clausen, T. (2004) Proteolysis as a regulatory mechanism. Annu Rev Genet. 38:709-24
Fitzpatrick, TB., Auweter, S., Kitzing, K., Clausen, T., Amrhein, N., Macheroux, P. (2004) Structural and functional impairment of an Old Yellow Enzyme homologue upon affinity tag incorporation. Protein Expr Purif. 36(2):280-91
Kurzbauer, R., Teis, D., de Araujo, ME., Maurer-Stroh, S., Eisenhaber, F., Bourenkov, GP., Bartunik, HD., Hekman, M., Rapp, UR., Huber, LA., Clausen, T. (2004) Crystal structure of the p14/MP1 scaffolding complex: how a twin couple attaches mitogen-activated protein kinase signaling to late endosomes. Proc Natl Acad Sci U S A. 101(30):10984-9
Vadivelu, SK., Kurzbauer, R., Dieplinger, B., Zweyer, M., Schafer, R., Wernig, A., Vietor, I., Huber, LA. (2004) Muscle regeneration and myogenic differentiation defects in mice lacking TIS7. Mol Cell Biol. 24(8):3514-25
Wilken, C., Kitzing, K., Kurzbauer, R., Ehrmann, M., Clausen, T. (2004) Crystal structure of the DegS stress sensor: How a PDZ domain recognizes misfolded protein and activates a protease. Cell. 117(4):483-94

2003

Groll, M., Clausen, T. (2003) Molecular shredders: how proteasomes fulfill their role. Curr Opin Struct Biol. 13(6):665-73
Kaiser, JT., Bruno, S., Clausen, T., Huber, R., Schiaretti, F., Mozzarelli, A., Kessler, D. (2003) Snapshots of the cystine lyase C-DES during catalysis. Studies in solution and in the crystalline state. J Biol Chem. 278(1):357-65

2002

Clausen, T., Southan, C., Ehrmann, M. (2002) The HtrA family of proteases: implications for protein composition and cell fate. Mol Cell. 10(3):443-55
Garrido-Franco, M., Ehlert, S., Messerschmidt, A., Marinkovic', S., Huber, R., Laber, B., Bourenkov, GP., Clausen, T. (2002) Structure and function of threonine synthase from yeast. J Biol Chem. 277(14):12396-405
Garrido-Franco, M., Laber, B., Huber, R., Clausen, T. (2002) Enzyme-ligand complexes of pyridoxine 5'-phosphate synthase: implications for substrate binding and catalysis. J Mol Biol. 321(4):601-12
Krojer, T., Garrido-Franco, M., Huber, R., Ehrmann, M., Clausen, T. (2002) Crystal structure of DegP (HtrA) reveals a new protease-chaperone machine. Nature. 416(6879):455-9

2001

Breithaupt, C., Strassner, J., Breitinger, U., Huber, R., Macheroux, P., Schaller, A., Clausen, T. (2001) X-ray structure of 12-oxophytodienoate reductase 1 provides structural insight into substrate binding and specificity within the family of OYE. Structure. 9(5):419-29
Breitinger, U., Clausen, T., Ehlert, S., Huber, R., Laber, B., Schmidt, F., Pohl, E., Messerschmidt, A. (2001) The three-dimensional structure of cystathionine beta-lyase from Arabidopsis and its substrate specificity. Plant Physiol. 126(2):631-42
Franco, MG., Laber, B., Huber, R., Clausen, T. (2001) Structural basis for the function of pyridoxine 5'-phosphate synthase. Structure. 9(3):245-53
Steegborn, C., Laber, B., Messerschmidt, A., Huber, R., Clausen, T. (2001) Crystal structures of cystathionine gamma-synthase inhibitor complexes rationalize the increased affinity of a novel inhibitor. J Mol Biol. 311(4):789-801

2000

Clausen, T., Kaiser, JT., Steegborn, C., Huber, R., Kessler, D. (2000) Crystal structure of the cystine C-S lyase from Synechocystis: stabilization of cysteine persulfide for FeS cluster biosynthesis. Proc Natl Acad Sci U S A. 97(8):3856-61
Clausen, T., Schlegel, A., Peist, R., Schneider, E., Steegborn, C., Chang, YS., Haase, A., Bourenkov, GP., Bartunik, HD., Boos, W. (2000) X-ray structure of MalY from Escherichia coli: a pyridoxal 5'-phosphate-dependent enzyme acting as a modulator in mal gene expression. EMBO J. 19(5):831-42
Garrido Franco, M., Huber, R., Schmidt, FS., Laber, B., Clausen, T. (2000) Crystallization and preliminary X-ray crystallographic analysis of PdxJ, the pyridoxine 5'-phosphate synthesizing enzyme. Acta Crystallogr D Biol Crystallogr. 56(Pt 8):1045-8
Kaiser, JT., Clausen, T., Bourenkow, GP., Bartunik, HD., Steinbacher, S., Huber, R. (2000) Crystal structure of a NifS-like protein from Thermotoga maritima: implications for iron sulphur cluster assembly. J Mol Biol. 297(2):451-64
rnSteegborn, C., Clausen, T. (2000) Specific inhibition of transsulfuration enzymes. Rec Res Developm Biochem. 2:191-207
Schreiber, V., Steegborn, C., Clausen, T., Boos, W., Richet, E. (2000) A new mechanism for the control of a prokaryotic transcriptional regulator: antagonistic binding of positive and negative effectors. Mol Microbiol. 35(4):765-76

1999

Clausen, T., Wahl, MC., Messerschmidt, A., Huber, R., Fuhrmann, JC., Laber, B., Streber, W., Steegborn, C. (1999) Cloning, purification and characterisation of cystathionine gamma-synthase from Nicotiana tabacum. Biol Chem. 380(10):1237-42
Laber, B., Maurer, W., Hanke, C., Gräfe, S., Ehlert, S., Messerschmidt, A., Clausen, T. (1999) Characterization of recombinant Arabidopsis thaliana threonine synthase. Eur J Biochem. 263(1):212-21
Steegborn, C., Clausen, T., Sondermann, P., Jacob, U., Worbs, M., Marinkovic, S., Huber, R., Wahl, MC. (1999) Kinetics and inhibition of recombinant human cystathionine gamma-lyase. Toward the rational control of transsulfuration. J Biol Chem. 274(18):12675-84
Steegborn, C., Messerschmidt, A., Laber, B., Streber, W., Huber, R., Clausen, T. (1999) The crystal structure of cystathionine gamma-synthase from Nicotiana tabacum reveals its substrate and reaction specificity. J Mol Biol. 290(5):983-96

1998

Clausen, T., Huber, R., Prade, L., Wahl, MC., Messerschmidt, A. (1998) Crystal structure of Escherichia coli cystathionine gamma-synthase at 1.5 A resolution. EMBO J. 17(23):6827-38

1997

Clausen, T., Huber, R., Messerschmidt, A., Pohlenz, HD., Laber, B. (1997) Slow-binding inhibition of Escherichia coli cystathionine beta-lyase by L-aminoethoxyvinylglycine: a kinetic and X-ray study. Biochemistry. 36(41):12633-43
Clausen, T., Laber, B., Messerschmidt, A. (1997) Mode of action of cystathionine beta-lyase. Biol Chem. 378(3-4):321-6
Jacob, U., Mack, M., Clausen, T., Huber, R., Buckel, W., Messerschmidt, A. (1997) Glutaconate CoA-transferase from Acidaminococcus fermentans: the crystal structure reveals homology with other CoA-transferases. Structure. 5(3):415-26
Wahl, MC., Huber, R., Prade, L., Marinkovic, S., Messerschmidt, A., Clausen, T. (1997) Cloning, purification, crystallization, and preliminary X-ray diffraction analysis of cystathionine gamma-synthase from E. coli. FEBS Lett. 414(3):492-6

1996

Clausen, T., Huber, R., Laber, B., Pohlenz, HD., Messerschmidt, A. (1996) Crystal structure of the pyridoxal-5'-phosphate dependent cystathionine beta-lyase from Escherichia coli at 1.83 A. J Mol Biol. 262(2):202-24
Laber, B., Clausen, T., Huber, R., Messerschmidt, A., Egner, U., Müller-Fahrnow, A., Pohlenz, HD. (1996) Cloning, purification, and crystallization of Escherichia coli cystathionine beta-lyase. FEBS Lett. 379(1):94-6

1995

Stenberg, K., Clausen, T., Lindqvist, Y., Macheroux, P. (1995) Involvement of Tyr24 and Trp108 in substrate binding and substrate specificity of glycolate oxidase. Eur J Biochem. 228(2):408-16