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42 Fig. 2: In vivo analysis of the fate of microinjected COPI vesicles. After microinjection into BSC-1 cells fluorescently labeled COPI vesicles fuse within 30 min with the Golgi. A) Rat mannosidase II (rat Mann II), a marker of the Golgi apparatus, originating from the injected vesicles can specifically be detected using an antibody specific for Mann II from rat. B) Two sets of proteins were labeled by Alexa-488, which behave like endogenous proteins after dissociation of the Golgi by BFA treatment. EMBL, and Werner Kühlbrandt, Frankfurt), protein chemistry, molecular biology, and quantitative nano-mass spectrometry of lipids. Research Highlights 1) We have discovered that not only one but three isoforms of coatomer, made up of combinations of two γ- and two ζ-COPs, are expressed in cells. These coatomer isoforms are differentially localized within the Golgi apparatus, strongly suggesting that they fulfill independent functions. We now succeeded in recombinant expression of all coatomer isoforms and are currently analyzing the protein and lipid composition of COPI vesicles generated in vitro using defined coatomer isoforms. 2) In our attempts to understand the molecular mechanisms of curvature formation in COPI vesicle budding, we have shown that coatomer discriminates endoplasmic reticulum residents from p24 proteins, with only the latter ones being able to induce a conformational change in coatomer that in our view initiates coat polymerization. Felix Wieland / Britta Brügger 3) We have show that Arf1-GTP dimerizes on membranes, and have identified an Arf1 mutant that is unable to dimerize, and is lethal when expressed in vivo. Strikingly, this mutant still recruits coatomer to membranes but does not support the formation of vesicles. Using an in vitro liposomal system, we found that dimeric Arf1- GTP induces positive curvature in membranes, whereas the monomeric mutant does not. Thus, activated ARF1 does not only serve as a GTP- switch in order to recruit coat proteins, but is also able to form positive curvature in membranes. 4) We have developed a platform for quantitative analysis of membrane lipids that has allowed us to determine lipidomes such as of HIV particles (with Hans-Georg Kräusslich, Heidelberg), of purified synaptic vesicles (with Reinhard Jahn, Göttingen), and of subcompartments of the brain of knock out mice (with Klaus-Armin Nave, Göttingen). Our research is supported by the German Research Council (SFB 638: Dynamics of mac- romolecular complexes in biosynthetic transport,
TR13: Membrane microdomains and their role in human disease, SPP1175: Dynamics of cellular membranes and their exploitation by viruses). Selected Publications 2004 - 2007 J. Langer, C.M. Roth, J. Béthune, E.H. Stoops, B. Brügger, D.-P. Herten, F.T. Wieland (2007) A conformational change in the alpha-subunit of coatomer induced by ligand binding to gamma-COP revealed using single-molecule FRET. Traffic, Traffic. Dec 25; [Epub ahead of print] C. M. Kassmann, C. Lappe-Siefke, M. Baes, B. Brügger, A. Mildner, H. B. Werner, O. Natt, T. Michaelis, M. Prinz, J. Frahm, K. A. Nave (2007). Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nat Genet. 39: 969-976. Z. Sun, F. Anderl, K. Fröhlich, L. Zhao, S. Hanke, B. Brügger, F. Wieland, J. Béthune (2007). Multiple and stepwise interactions between coatomer and ADP-ribosylation factor-1 (Arf1)-GTP. Traffic 8: 582-593. J. Moelleken, J. Malsam, M.J. Betts, A. Movafeghi, I. Reckmann, I. Meissner, A. Hellwig, R.B. Russell, T. Söllner, B. Brügger, F. Wieland (2007). Differential localization of coatomer complexes isoforms within the Golgi apparatus. Proc. Natl. Acad. Sci. USA 104: 4425-4430. B. Brügger, B. Glass, P. Haberkant, I. Leibrecht, F. Wieland, and H.-G. Kräusslich (2006). The HIV lipidome: A raft with an unusual composition. Proc. Natl. Acad. Sci. USA 103: 2641-2646. J. Béthune, M. Kol, J. Hoffmann, I. Reckmann, B. Brügger, F. Wieland (2006). Coatomer, the coat protein of COPI transport vesicles, discriminates endoplasmic reticulum residents from p24 proteins. Mol. Cell. Biol. 26: 8011-8021. J. Béthune, F. Wieland, J. Moelleken (2006): COPI-mediated transport. J. Membr. Biol. 211: 65-79. S. Takamori, M. Holt, K. Stenius, E.A. Lemke, M. Grønborg, D. Riedel, H. Urlaub, S. Schenck, B. Brügger, P. Ringler, S.A. Müller, B. Rammner, F. Gräter, J.S. Hub, B.L. De Groot, G. Mieskes, Y. Moriyama, J. Klingauf, H. Grubmüller, J. Heuser, F. Wieland, R. Jahn (2006). Molecular Anatomy of a Trafficking Organelle. Cell 127: 831-846. G. Saher, B. Brügger, C. Lappe-Siefke, W. Möbius, R. Tozawa, M. C. Wehr, F. Wieland, S. Ishibashi, K.-A. Nave (2005). High cholesterol level is essential for myelin membrane growth. Nature Neurosci. 8: 468-475. D. Wegmann, P. Hess, C. Baier, F. T. Wieland, C. Reinhard (2004). Novel isotypic γ/ζ-subunits reveal three coatomer complexes in mammals. Mol. Cell. Biol. 24: 1070-1080. Awards and Honors Felix Wieland 1993 Honorary Member of Charité, Medical Faculty of the Humboldt University, Berlin Since 2000 EMBO Member 2001 Heinrich-Wieland Award since 2003 Member of Deutsche Akademie der Naturforscher Leopoldina 2006 Feldberg Foundation Award Felix Wieland Biochemie-Zentrum der Universität Heidelberg (BZH) Im Neuenheimer Feld 328 D-69120 Heidelberg Phone: +49 (0)6221-54 4150 Fax: +49 (0)6221-54 4366 E-mail: felix.wieland@bzh.uni-heidelberg.de Britta Brügger Biochemie-Zentrum der Universität Heidelberg (BZH) Im Neuenheimer Feld 328 D-69120 Heidelberg Phone: +49 (0)6221-54 5426 Fax: +49 (0)6221-54 4366 E-mail: britta.bruegger@bzh.uni-heidelberg.de Felix Wieland / Britta Brügger 43
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