SFB 642: GTP- and ATP-dependent Membrane Processes
Medicine
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) 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. and Wittinghofer A.
(See online at https://dx.doi.org/10.1038/nature03604) - (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 H.W., Grunau S., Rosenkranz K., Girzalsky W., Erdmann R.
(See online at https://doi.org/10.1038/ncb1281) - (2007) Structural insight into filament formation by mammalian septins. Nature 449, 311-315
Sirajuddin M., Farkasovsky M., Hauer F., Kühlmann D., Macara I. G., Weyand M., Stark H. and Wittinghofer A.
(See online at https://doi.org/10.1038/nature06052) - (2008) The crystal structure of the Ran-Nup153 complex: A General Ran docking site at the nuclear pore complex. Structure 16, 1116-1125
Schrader N., Koerner C., Koessmeier K., Bangert J., Wittinghofer A., Stoll R. and Vetter I.R.
(See online at https://dx.doi.org/10.1016/j.str.2008.03.014) - (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 C., Kallenbach A., Suveyzdis Y., Wittinghofer A., Gerwert K.
(See online at https://dx.doi.org/10.1073/pnas.0712095105) - (2009) Analysis of the eukaryotic prenylome by isoprenoid affinity tagging. Nature chemical biology 5, 227-235
Nguyen U.T., Guo Z., Delon C., Wu Y., Deraeve C., Franzel B., Bon R.S., Blankenfeldt W., Goody R.S., Waldmann H., Wolters D. and Alexandrov K.
(See online at https://dx.doi.org/10.1038/nchembio.149) - (2010) The Palmitoylation Machinery is a Spatially Organizing System for Peripheral Membrane Proteins. Cell, 141, 458-471
Rocks O., Gerauer M., Vartak N., Koch S., Huang Z.P., Pechlivanis M., Kuhlmann J., Brunsveld L., Chandra A., Ellinger B., Waldmann H., Bastiaens P. I. H.
(See online at https://dx.doi.org/10.1016/j.cell.2010.04.007) - (2010) The structure of an Arf-ArfGAP complex reveals a Ca2+-regulatory mechanism. Cell 141, 812-821
Ismail S.A., Vetter I.R., Sot B. and Wittinghofer A.
(See online at https://doi.org/10.1016/j.cell.2010.03.051) - (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 S.A., Chen Y.X., Rusinova A., Chandra A., Bierbaum M., Gremer L., Triola G., Waldmann H., Bas-tiaens P.I., Wittinghofer A.
(See online at https://dx.doi.org/10.1038/nchembio.686) - (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 K., Langklotz S., Thomanek N., Narberhaus F.
(See online at https://doi.org/10.1074/jbc.M112.388470) - (2012) Catalytic Mechanism of a Mammalian Rab•RabGAP Complex in Atomic Detail. Proc. Natl. Acad. Sci., 109 (52), 21348-21353
Gavriljuk K., Gazdag E. M., Itzen A., Kötting C., Goody R. S., Gerwert K.
(See online at https://doi.org/10.1073/pnas.1214431110) - (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 C., Rosenblad M., Ziehe D., Garcia-Petit C., Schrader L., Kock K., Richter C., Klinkert B., Nar-berhaus F., Herrmann C., Hofmann E., Aronsson H. and Schünemann D.
(See online at https://doi.org/10.1105/tpc.112.102996) - (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, F., Suveyzdis Y., Kötting C., Gerwert K. and Hofmann E.
(See online at https://doi.org/10.1074/jbc.M112.359208) - (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 M., Jockers K.F., Düppe P.M., Autzen J., Potheraveedu V.N., Ince S., Yip K.T., Heumann R., Herrmann C., Scherkenbeck J., Stoll R.
(See online at https://doi.org/10.1021/jm401291q) - (2013) Small molecule inhibition of the Kras-PDEδ interaction impairs oncogenic KRAS signalling. Nature 497, 638-642
Zimmermann G., Papke B., Ismail S., Vartak N., Chandra A., Hoffmann M., Hahn S. A., Triola G., Wittinghofer A., Bastiaens P. I. H., Waldmann H.
(See online at https://doi.org/10.1038/nature12205) - (2014) The interdependence of membrane-shape and signal processing in cells. Cell. 2014 Mar 13;156(6):1132-1138
Schmick M., Bastiaens P.I.H.
(See online at https://doi.org/10.1016/j.cell.2014.02.007) - (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 T., Jenrich S., Brucker S., Vetter I.R., Gerwert K. and Kötting C.
(See online at https://doi.org/10.1074/jbc.M115.648071) - (2015) Locking GTPases covalently in their functional states. Nat. Comm. 6: 7773
Wiegandt D., Vieweg S., Hofmann F., Koch D., Li F., Wu Y., Itzen A., Müller M.P., Goody R.S.
(See online at https://doi.org/10.1038/ncomms8773) - (2015) Molecular snapshots of the Pex1/6 AAA+ complex in action. Nat Commun 6, 7331
Ciniawsky S., Grimm I., Saffian D., Girzalsky W., Erdmann R., Wendler P.
(See online at https://doi.org/10.1038/ncomms8331) - (2016) Functional Charac-terization of the Odorant Receptor 51E2 in Human Melanocytes. J Biol Chem. 2016 Aug 19;291(34):17772-86
Gelis L., Jovancevic N., Veitinger S., Mandal B., Arndt H.D., Neuhaus E.M., Hatt H.
(See online at https://doi.org/10.1074/jbc.M116.734517) - (2016) Mechanism of the intrinsic arginine finger in heterotrimeric G proteins. PNAS, 50 (113), E8041-E8050
Mann D., Teuber C., Tennigkeit S.A., Schröter G., Gerwert K., Kötting C.
(See online at https://doi.org/10.1073/pnas.1612394113) - (2016) Regulation of oligodendrocyte precursor maintenance by chondroitin sulphate glycosaminoglycans. GLIA 64, 270-286
Karus M., Czopka T., Ulc A., Ehrlich M., Hennen E., Mizhorova M., Qamar N., Brüstle O. and Faissner A.
(See online at https://doi.org/10.1002/glia.22928)
