SFB 635:  Posttranslational Control of Protein Function

• Subject Area: Biology ; Medicine
• Term: from 2003 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5485912

• Final Report Year: 2016

Final Report Abstract

The Collaborative Research Centre (CRC) 635 was built on information that became available with the sequencing of genomes of an increasing number of organisms including human. These genome projects revealed a surprisingly small number of genes and thus suggested that posttranslational control mechanisms are of utmost importance for maintaining organismal complexity and for promoting adaptive responses at a cellular and organismal level. This led to the central aim of the CRC 635: to decipher mechanisms determining the function of proteins at a posttranslational level. The CRC 635 has taken an interdisciplinary approach to tackle the complexity of posttranslational regulatory networks and brought together research groups using genetic, cell biological and biochemical methods in the context of evolutionary diverse model organisms, such as bacteria, yeast, Drosophila, Arabidopsis and mice. The CRC 635 focused on three general regulatory principles that defined closely interconnected research areas: the regulation by covalent protein modification, the regulation by dynamic protein assembly, and the regulation by proteolytic processes that influence the stability or activity of proteins. Groups within the CRC 635 addressed different physiological processes, which included determination of flowering time in plants, vesicular trafficking, or the biogenesis of cell organelles, but also spermatogenesis or processes that determine neuronal activities. This broad and interdisciplinary approach allowed identifying conserved principles in regulation and, at the same time, variations thereof as adjustment to specific demands. The parallel investigation of regulatory processes in various model organisms proved to be very beneficial, as the general relevance of discoveries made in one model could be quickly examined in other systems within the CRC. During the initial years of the funding period, many projects employed genetic methods to explore the role of posttranslational control mechanisms in different physiological contexts. These studies formed an important basis for a detailed mechanistic analysis of many of the identified processes in subsequent years. Biochemical approaches became of utmost importance in the last funding period, when the function of specific posttranslational modifications or other regulatory mechanisms was studied at a molecular level, often based on structural information that became available to the scientific community or was obtained within the CRC. Together, the research projects within the CRC 635 revealed a close relationship and crosstalk of different regulatory mechanisms which stimulated scientific exchange and collaboration between various research groups. The funding period of the CRC 635 coincided with major technical developments, in particular in proteomic approaches and live cell imaging, which were instrumental for the success of the individual research projects within the CRC. It was therefore an important strategic aim of the CRC635 to establish technology platforms at the University of Cologne, which offer state-of-the-art service to the local research community. The dynamic development of the research field is also reflected on dynamic developments in personnel, which worked within the CRC 635 and in the Cologne research environment. The CRC 635 therefore succeeded to provide important new insight into cellular mechanisms regulating protein function at a posttranslational level, but also contributed significantly to the structural development of the scientific research environment in Cologne.

Publications

• (2005). Phosphatidylinositol-(4,5)-bisphosphate regulates sorting signal recognition by the clathrin-associated adaptor complex AP2. Mol. Cell 18, 519-531
  Höning, S., Ricotta, D., Krauss, M., Späte, K., Spolaore, B., Motley, A., Robinson, M., Robinson, C., Haucke, V., and Owen, D.
  
• (2005). The m-AAA protease defective in hereditary spastic paraplegia controls ribosome assembly in mitochondria. Cell 123, 277-289
  Nolden, M., Ehses, S., Koppen, M., Bernacchia, A., Rugarli, E. I., and Langer, T.
  
• (2006). Role of SGT1 in resistance protein accumulation in plant immunity. EMBO J. 25, 2007-2016
  Azevedo, C., Betsuyaku, S., Peart, J., Takahashi, A., Noël, L., Sadanandom, A., Casais, C., Parker, J. and Shirasu, K.
  
• (2014). Natural variation reveals that intracellular distribution of ELF3 protein is associated with function in the circadian clock. eLife 3, e02206
  Anwer, M.U., Boikoglou, E., Herrero, E., Hallstein, M., Davis, A.M., James, G.V., Nagy, F., and Davis, S.J.
  
• (2007). Interaction between SGT1 and cytosolic HSC70 chaperones regulates Arabidopsis immune responses. Plant Cell 19, 4061-4076
  Noël, L.D., Cagna, G., Stuttmann, J., Wirthmüller, L., Betsuyaku, S., Witte, C.P., Bhat, R., Pochon, N., Colby, T., and Parker, J.E.
  
• (2007). Ubiquitin-dependent proteolytic control of SUMO conjugates. J. Biol. Chem. 282, 34167-34175
  Uzunova, K., Göttsche, K., Miteva, M., Weißhaar, S.R., Glanemann, C., Schnellhardt, M., Niessen, M., Scheel, M., Hofmann, K., Johnson, E.S., Praefcke, G.J.K., and Dohmen, R.J.
  
• (2008). A structural explanation for the binding of endocytic dileucine motifs by the AP2 complex. Nature 18, 976-9
  Kelly, B.T., McCoy, A.J., Späte, K., Miller, S.E., Evans, P.R., Höning, S., and Owen, D.J.
  
• (2008). Arabidopsis COP1 shapes the temporal pattern of CO accumulation conferring a photoperiodic flowering response. EMBO J. 27, 1277-1288
  Jang, S., Marchal, V., Panigrahi, K.C.S., Wenkel, S., Soppe, W., Deng, X.W., Valverde, F., and Coupland, G.
  
• (2009). An intersubunit signaling network coordinates ATP hydrolysis by m-AAA proteases. Mol. Cell. 35, 574-585
  Augustin, S., Gerdes, F., Lee, S., Tsai, F.T., Langer, T., and Tatsuta T.
  
• (2009). PLRG1 is an essential regulator of cell proliferation and apoptosis during vertebrate development and tissue homeostasis. Mol. Cell. Biol. 29, 3173-3185
  Kleinridders, A., Pogoda, H.M., Irlenbusch, S., Smyth, N., Koncz, C., Hammerschmidt, M., and Brüning, J.C.
  
• (2010). A novel conserved phosphotyrosine motif in the Drosophila FGF-signalling adaptor Dof with a redundant role in signal transmission. Mol. Cell Biol. 30, 2017-2027
  Csiszar, A., Vogelsang, E., Beug, H., and Leptin, M.
  
• (2010). Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr. Biol. 20, 143-148
  Arndt, V., Dick, N., Tawo, R., Dreiseidler, M., Wenzel, D., Hesse, M., Fürst, D.O., Saftig, P., Saint, R., Fleischmann, B.K., Hoch, M., and Höhfeld, J.
  
• (2010). DivIC stabilizes FtsL against RasP cleavage. J. Bacteriol. 192, 5260-5263
  Wadenpohl, I. and Bramkamp, M.
  
• (2010). Proteome-wide screens for small ubiquitin-like modifier (SUMO) substrates identify Arabidopsis proteins implicated in diverse biological processes. Proc. Natl. Acad. Sci. USA 107, 17415-17420
  Elrouby, N. and Coupland, G.
  
• (2011). Bacillus subtilis dynamin-like protein catalyzes magnesium assisted membrane fusion. Mol. Microbiol. 79, 1294-1304
  Bürmann, F., Ebert, N., van Baarle, S., and Bramkamp, M.
  
• (2011). Light-exposure of Arabidopsis seedlings causes rapid de-stabilization as well as selective post-translational inactivation of the repressor of photo-morphogenesis SPA2. Plant J. 65, 712723
  Balcerowicz, M., Fittinghoff, K., Wirthmueller, L., Maier, A., Fackendahl, P., Fiene, G., Koncz, C., and Hoecker, U.
  
• (2011). Presequence-dependent folding ensures MRPL32 processing by the m-AAA protease in mitochondria. EMBO J. 30, 2545-2556
  Bonn, F., Tatsuta, T., Petrungaro, C., Riemer, J., and Langer, T.
  
• (2011). Regulation of glycine receptor diffusion properties and gephyrin interactions by protein kinase C. EMBO J. 30, 3842-3853
  Specht, C.G., Grunewald, N., Pascual, O., Rostgaard, N., Schwarz, G., and Triller, A.
  
• (2012). A Toxoplasma gondii pseudokinase inhibits host IRG resistance proteins. PloS Biol. 10, e1001358
  Fleckenstein, M., Reese, M.L., Boothroyd, J.C., Howard, J.C., and Steinfeldt, T.
  
• (2012). Artificial ubiquitylation is sufficient for sorting of a plasma membrane ATPase to the vacuolar lumen of Arabidopsis cells. Planta 236, 63-77
  Herberth, S., Shahriari, M., Bruderek, M., Hessner, F., Müller, B., Hülskamp, M., and Schellmann, S.
  
• (2012). TIME FOR COFFEE represses accumulation of the MYC2 transcription factor to provide time-of-day regulation of jasmonate signaling in Arabidopsis. Plant Cell 24, 2470-2482
  Shin, J., Heidrich, K., Sanchez-Villareal, A., Parker, J., and Davis, S.J.
  
• (2013). Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy. Curr. Biol. 23, 430-435
  Ulbricht, A., Eppler, F.J., Tapia, V.E., van der Ven, P.F., Hampe, N., Hersch, N., Vakeel, P., Stadel, D., Haas, A., Saftig, P., Behrends, C., Fürst, D.O., Volkmer, R., Hoffmann, B., Kolanus, W., and Höhfeld, J.
  
• (2013). Light and the E3 ubiquitin ligase COP1/SPA control the protein stability of the MYB transcription factors PAP1 and PAP2 involved in anthocyanin accumulation in Arabidopsis. Plant J. 74, 638-651
  Maier, A., Schrader, A., Kokkelink, L., Falke, C., Welter, B., Iniesto, E., Rubio, V., Uhrig, J.F., Hülskamp, M., and Hoecker, U.
  
• (2013). Reciprocal virulence and resistance polymorphism in the relationship between Toxoplasma gondii and the house mouse. eLife 2:e01298
  Lilue, J., Mueller, U.B., Steinfeldt, T., and Howard, J.C.
  
• (2013). Regulation of the CRL4(Cdt2) ubiquitin ligase and cell-cycle exit by the SCF(Fbxo11) ubiquitin ligase. Mol. Cell 49, 1159-1166
  Rossi, M., Duan, S., Jeong, Y.T., Horn, M., Saraf, A., Florens, L., Washburn, M.P., Antebi, A., and Pagano, M.
  
• (2013). Structural basis for signaling by exclusive EDS1 heteromeric complexes with SAG101 or PAD4 in plant innate immunity. Cell Host Microbe 14, 619-630
  Wagner, S., Stuttmann, J., Rietz, S., Guerois, R., Brunstein, E., Bautor, J., Niefind, K., and Parker, J.E.
  
• (2013). The myosin chaperone UNC-45 is organized in tandem modules to support myofilament formation in C. elegans. Cell 152, 183-195
  Gazda, L., Pokrzywa, W., Hellerschmied, D., Löwe, T., Forné, I., Mueller-Planitz, F., Hoppe, T., and Clausen, T.
  
• (2013). TIME FOR COFFEE is an essential component in the maintenance of metabolic homeostasis in Arabidopsis thaliana. Plant J. 76, 188-200
  Sanchez-Villarreal, A., Shin, J., Bujdoso, N., Obata, T., Neumann, U., Du, S.X., Ding, Z., Davis, A.M., Shindo, T., Schmelzer, E., Sulpice, R., Nunes-Nesi, A., Stitt, M., Fernie, A.R., and Davis, S.J.
  
• (2014). 3' UTR length and messenger ribonucleoprotein composition determine endocleavage efficiencies at termination codons. Cell Rep. 9, 555-568
  Boehm, V., Haberman, N., Ottens, F., Ule, J., and Gehring, N.H.
  
• (2014). AP2 controls clathrin polymerization with a membrane-activated switch. Science 345, 459-463
  Kelly, T.K., Graham, S.C., Liska, N., Dannhauser, P.N., Höning, S., Ungewickell, E.J., and Owen, D.J.
  
• (2014). Distinct roles for JNK and IKK activation in agouti-related peptide neurons in the development of obesity and insulin resistance. Cell Rep. 9, 1495-506
  Tsaousidou, E., Paeger, L., Belgardt, B.F., Pal, M., Wunderlich, C.M., Brönneke, H., Collienne, U., Hampel, B., Wunderlich, F.T., Schmidt-Supprian, M., Kloppenburg, P., and Brüning, J.C.
  
• (2014). DRE-1/FBXO11-dependent degradation of BLMP-1/BLIMP-1 governs C. elegans developmental timing and maturation. Dev. Cell 28, 697-710
  Horn, M., Geisen, C., Cermak, L., Becker, B., Nakamura, S., Klein, C., Pagano, M., and Antebi, A.
  
• (2014). Hexosamine pathway metabolites enhance protein quality control and prolong life. Cell 156, 1167-1178
  Denzel, M.S., Storm, N.J., Gutschmidt, A., Baddi, R., Hinze, Y., Jarosch, E., Sommer, T., Hoppe, T., and Antebi, A.
  
• (2014). HSP70-binding protein HSPBP1 regulates chaperone expression at a posttranslational level and is essential for spermatogenesis. Mol. Biol. Cell 25, 2260-2271
  Rogon, C., Ulbricht, A., Hesse, M., Alberti, S., Vijayaraj, P., Best, D., Adams, I.R., Magin, T.M., Fleischmann, B.K., and Höhfeld, J.
  
• (2014). Phosphoproteomic analysis reveals regulatory mechanisms at the kidney filtration barrier. J. Am. Soc. Nephrol. 25, 1509-1522
  Rinschen, M.M., Wu, X., König, T., Pisitkun, T., Hagmann, H., Pahmeyer, C., Lamkemeyer, T., Kohli, P., Schnell, N., Schermer, B., Dryer, S., Brooks, B.R., Beltrao, P., Krueger, M., Brinkkoetter, P.T., and Benzing, T.
  
• (2015). CALM regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature. Dev. Cell 33, 163-175
  Miller, S.E., Mathiasen, S., Bright, N. A., Pierre, F., Kelly, B.T., Kladt, N., Schauss, A., Merrifield, C. J., Stamou, D., Höning, S., and Owen, D.J.
  
• (2015). Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure. EMBO Mol. Med. 7, 275-287
  Ising, C., Koeler, S., Braehler, S., Merkwirth, C., Höhne, M., Baris, O.R., Hagmann, H., Kann, M., Fabretti, F., Dafinger, C., Bloch, W., Schermer, B., Linkermann, A., Brüning, J.C., Kurschat, C., Müller, R.U., Wiesner, R., Langer, T., Benzing, T., and Brinkkötter, P.T.
  
• (2015). Small GTP-binding protein Ran is regulated by posttranslational lysine-acetylation. Proc. Natl. Acad. Sci. U. S. A. 112, E3679-3688
  de Boor, S., Knyphausen, P., Kuhlmann, N., Wroblowski, S., Brenig, J., Nolte, H., Krüger, M., and Lammers, M.
  
• (2016). RhoGDIα acetylation at K127 and K141 affects binding toward nonprenylated RhoA. Biochemistry 55, 304-312
  Kuhlmann, N., Wroblowski, S., Scislowski, L., and Lammers, M.