SFB 642:  GTP- and ATP-dependent Membrane Processes

• Subject Area: Biology ; Medicine
• Term: from 2004 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5486123

• Final Report Year: 2017

Final Report Abstract

The SFB 642 contributed to a detailed understanding of GTP- and ATP-dependent signal transduction and transport processes at biological membranes at different scales. Single recombinant proteins up to complex protein-interaction networks in living cells have been studied. The complex, dynamic interplay between the proteins at membranes have been elucidated here with highest possible spatiotemporal resolution. The orchestration of expertise within the SFB 642 provided the unique opportunity to start with a detailed understanding of molecular reaction mechanisms and interactions of proteins in vitro in order to arrive at a thorough comprehension of how these processes are being integrated into the entire activity of the living cell. Determination of the three-dimensional structure of recombinant proteins in vitro is always a milestone in protein sciences, but the ultimate goal is the detailed understanding of the dynamic interplay of the proteins in vivo. As such a broad approach is a prerequisite to elucidate a biological issue of this complexity, a large consortium like the SFB was needed to succeed over different scales. Besides X-ray structure analysis and nuclear magnetic resonance (NMR)-spectroscopy also label-free time-resolved Fourier-Transform-Infra-Red (FTIR)-spectroscopy in combination with biomolecular simulations were the key experimental approaches by the SFB 642 to provide not only ‘snapshots’ but complete ‘movies’ of protein mechanisms and interactions. Chemical biology provides probes for fluorescence studies and drug candidates for a targeted therapy. Most of the projects were arranged around small GTPases of the Ras superfamily and their effectors. During the founding period PIs of the SFB 642 solved the structural models of 427 proteins deposited in the PDB data base, mostly of small G-proteins and their interaction partners. Furthermore, the projects contributed to a deeper understanding of the membrane insertion of small G-proteins, anchoring and extraction, especially by PDEδ. In addition Gα of heterotrimeric G-proteins which share the same G-domain motive with the Ras superfamily were studied. Besides GTPases the structures and functions of membrane-bound ATPases, especially peroxisomal proteins, were also studied in great detail. Mutations of the involved proteins can cause serious diseases. Thus, the issues addressed by SFB 642 provide a deeper understanding of these processes and contribute to precision medicine.

Publications

• (2005). Functional role of the AAA peroxins in dislocation of the cycling PTS1 receptor back to the cytosol. Nat Cell Biol 7 (8), 817- 22
  Platta, Harald W.; Grunau, Silke; Rosenkranz, Katja; Girzalsky, Wolfgang & Erdmann, Ralf
  
• (2005) Structural and mechanistic insights into the interaction between Rho and mammalian Dia. Nature 435, 513- 518
  Rose, R.; Weyand, M.; Lammers, M.; Ishizaki, T.; Ahmadian, M. R. & Wittinghofer, A.
  
• (2007) Structural insight into filament formation by mammalian septins. Nature 449, 311-315
  Sirajuddin, Minhajuddin; Farkasovsky, Marian; Hauer, Florian; Kühlmann, Dorothee; Macara, Ian G.; Weyand, Michael; Stark, Holger & Wittinghofer, Alfred
  
• (2008) The crystal structure of the Ran-Nup153 complex: A General Ran docking site at the nuclear pore complex. Structure 16, 1116-1125
  Schrader, Nils; Koerner, Carolin; Koessmeier, Katja; Bangert, Jan-Amadé; Wittinghofer, Alfred; Stoll, Raphael & Vetter, Ingrid R.
  
• (2008) The GAP arginine finger movement into the catalytic site of Ras increases the activation entropy. Proc. Natl. Acad. Sci., 105, No. 17, 6260-6265
  Kötting, Carsten; Kallenbach, Angela; Suveyzdis, Yan; Wittinghofer, Alfred & Gerwert, Klaus
  
• (2009) Analysis of the eukaryotic prenylome by isoprenoid affinity tagging. Nature chemical biology 5, 227-235
  Nguyen, Uyen T T; Guo, Zhong; Delon, Christine; Wu, Yaowen; Deraeve, Celine; Fränzel, Benjamin; Bon, Robin S; Blankenfeldt, Wulf; Goody, Roger S; Waldmann, Herbert; Wolters, Dirk & Alexandrov, Kirill
  
• (2010) The Palmitoylation Machinery is a Spatially Organizing System for Peripheral Membrane Proteins. Cell, 141, 458-471
  Rocks, Oliver; Gerauer, Marc; Vartak, Nachiket; Koch, Sebastian; Huang, Zhi-Ping; Pechlivanis, Markos; Kuhlmann, Jürgen; Brunsveld, Lucas; Chandra, Anchal; Ellinger, Bernhard; Waldmann, Herbert & Bastiaens, Philippe I.H.
  
• (2010) The structure of an Arf-ArfGAP complex reveals a Ca2+-regulatory mechanism. Cell 141, 812-821
  Ismail, Shehab A.; Vetter, Ingrid R.; Sot, Begona & Wittinghofer, Alfred
  
• (2011) Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesyl-ated cargo. Nat Chem Biol. 2011 Oct 16;7(12):942-9
  Ismail, Shehab A; Chen, Yong-Xiang; Rusinova, Alexandra; Chandra, Anchal; Bierbaum, Martin; Gremer, Lothar; Triola, Gemma; Waldmann, Herbert; Bastiaens, Philippe I H & Wittinghofer, Alfred
  
• (2012) A trapping approach reveals novel substrates and physiological functions of the essential protease FtsH in Escherichia coli. J. Biol. Chem. 287:42962-42971
  Westphal, Kai; Langklotz, Sina; Thomanek, Nikolas & Narberhaus, Franz
  
• (2012) Catalytic Mechanism of a Mammalian Rab•RabGAP Complex in Atomic Detail. Proc. Natl. Acad. Sci., 109 (52), 21348-21353
  Gavriljuk, Konstantin; Gazdag, Emerich-Mihai; Itzen, Aymelt; Kötting, Carsten; Goody, Roger S. & Gerwert, Klaus
  
• (2012) Evolution from the prokaryotic to the higher plant chloroplast signal recognition particle: the signal recognition particle RNA is conserved in plastids of a wide range of photosynthetic organisms. Plant Cell 24:4819-4836
  Träger, Chantal; Rosenblad, Magnus Alm; Ziehe, Dominik; Garcia-Petit, Christel; Schrader, Lukas; Kock, Klaus; Vera Richter, Christine; Klinkert, Birgit; Narberhaus, Franz; Herrmann, Christian; Hofmann, Eckhard; Aronsson, Henrik & Schünemann, Danja
  
• (2012) Time-Resolved Fourier Transform Infrared Spectroscopy of the Nucleotide-Binding Domain from the ATP-Binding Cassette Transporter MsbA ATP Hydrolysis Is the Rate-Limiting Step in the Catalytic Cycle. Journal of Biological Chemistry 287 (28): 23923–31
  Syberg, Falk; Suveyzdis, Yan; Kötting, Carsten; Gerwert, Klaus & Hofmann, Eckhard
  
• (2013) Bisphenol A binds to Ras proteins and competes with guanine nucleotide exchange: implications for GTPase-selective antagonists. J Med Chem. 2013 Dec 12;56(23):9664-72
  Schöpel, Miriam; Jockers, Katharina F. G.; Düppe, Peter M.; Autzen, Jasmin; Potheraveedu, Veena N.; Ince, Semra; Yip, King Tuo; Heumann, Rolf; Herrmann, Christian; Scherkenbeck, Jürgen & Stoll, Raphael
  
• (2013) Small molecule inhibition of the Kras-PDEδ interaction impairs oncogenic KRAS signalling. Nature 497, 638-642
  Zimmermann, Gunther; Papke, Björn; Ismail, Shehab; Vartak, Nachiket; Chandra, Anchal; Hoffmann, Maike; Hahn, Stephan A.; Triola, Gemma; Wittinghofer, Alfred; Bastiaens, Philippe I. H. & Waldmann, Herbert
  
• (2014) The interdependence of membrane-shape and signal processing in cells. Cell. 2014 Mar 13;156(6):1132-1138
  Schmick, Malte & Bastiaens, Philippe I.H.
  
• (2015) Catalysis of GTP Hydrolysis by Small GTPases at Atomic Detail by Integration of X-ray Crystallography, Experimental, and Theoretical IR Spectroscopy. JBC 290, 24079-24090
  Rudack, Till; Jenrich, Sarah; Brucker, Sven; Vetter, Ingrid R.; Gerwert, Klaus & Kötting, Carsten
  
• (2015) Locking GTPases covalently in their functional states. Nat. Comm. 6: 7773
  Wiegandt, David; Vieweg, Sophie; Hofmann, Frank; Koch, Daniel; Li, Fu; Wu, Yao-Wen; Itzen, Aymelt; Müller, Matthias P. & Goody, Roger S.
  
• (2015) Molecular snapshots of the Pex1/6 AAA+ complex in action. Nat Commun 6, 7331
  Ciniawsky, Susanne; Grimm, Immanuel; Saffian, Delia; Girzalsky, Wolfgang; Erdmann, Ralf & Wendler, Petra
  
• (2016) Regulation of oligodendrocyte precursor maintenance by chondroitin sulphate glycosaminoglycans. GLIA 64, 270-286
  Karus, Michael; Ulc, Annika; Ehrlich, Marc; Czopka, Tim; Hennen, Eva; Fischer, Julia; Mizhorova, Marija; Qamar, Naila; Brüstle, Oliver & Faissner, Andreas
  
• (2016) Functional Charac-terization of the Odorant Receptor 51E2 in Human Melanocytes. J Biol Chem. 2016 Aug 19;291(34):17772-86
  Gelis, Lian; Jovancevic, Nikolina; Veitinger, Sophie; Mandal, Bhubaneswar; Arndt, Hans-Dieter; Neuhaus, Eva M. & Hatt, Hanns
  
• (2016) Mechanism of the intrinsic arginine finger in heterotrimeric G proteins. PNAS, 50 (113), E8041-E8050
  Mann, Daniel; Teuber, Christian; Tennigkeit, Stefan A.; Schröter, Grit; Gerwert, Klaus & Kötting, Carsten