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Christian Ungermann Goal Our group is interested in the mechanism of organelle biogenesis membrane fusion within the endolysosomal system. We use the vacuole of the yeast Saccharomyces cerevisae as a model system to study the role of tethering factors, SNAREs and their regulators in an organelle fusion reaction. Our work revealed that endosome-vacuole biogenesis is deter- mined by two homolgous tethering factors, called CORVET and HOPS. A second focus of the lab is the analysis of protein palmitoylation in membrane fusion. Background Organelles of the secretory and the endocytic pathway are connected by vesicles that transport proteins and lipids. Vesicles are formed on a donor compartment with the help of coat proteins and deliver their cargo upon fusion with the target organelle (Fig. 1). Between endosome and lysosome, transport also occurs by organelle maturation rather than vesicular transport (Ungermann and Langosch, 2005). The yeast vacuole represents a perfect system to study membrane fusion and biogenesis. Yeast vacuoles are dynamic organelles that undergo fission and fusion in response to osmotic changes, 36 Christian Ungermann 1996 PhD, University of Munich, Germany 1996-1999 Post-doctoral research fellow with Prof. William Wickner, Dartmouth Medical School, Hanover, NH, U.S.A. 2002 EMBO Young Investigator award 2003 Appointment as university lecturer (venia legendi in Biochemistry), Medical Faculty, University of Heidelberg, 1999-2005 Group leader at the Biochemie-Zentrum der Universität Heidelberg (BZH), Germany Since 2006 Full Professor at the Department of Biology, University of Osnabrück, Germany Vacuole biogenesis and protein palmitoylation and can be monitored in vitro and in vivo. Fusion of endosomes and vacuoles depends on the initial membrane contact mediated by Rab GTPases and tethering factors (at the endosome CORVET, at the vacuole HOPS) and SNAREs, which drive lipid-bilayer mixing. Research Highlights Within the last three years the lab shifted its focus towards tethering factors and their role in endolysosomal biogenesis. We identified a kinase (Yck3) that modifies a subunit of the vacuolar HOPS complex and regulates fusion (LaGrassa et al., 2005), and established methods to isolate the endosomal and vacuolar tethering complexes (Fig. 2; Peplowska et al., 2007). The novel endosomal CORVET complex and the HOPS complex share four subunits, suggesting that they can interconvert – an issue that we are presently focussing on. Most SNAREs are membrane proteins with a C-terminal transmembrane domain, followed by a coiled-coil/SNARE domain and a variable N-terminal domain (NTD). In collaboration with Dieter Langosch (TU Munich), we could show that SNARE dimerization is critical for the hemifusion to fusion transition (Hofmann et al., 2006). The function of this dimerization is still unclear.
Fig. 1: Model of vesicular transport (Ungermann and Langosch, 2005). Several regulators of fusion are peripheral membrane protein, and some carry lipid modifications. We could show that palmitoylation is required for function of the fusion factor Vac8 (Subramanian et al., 2006), and focus presently on the role of the vacuolar acyltransferase Pfa3 (Hou et al., in preparation). Fig. 2: Isolation of the endosomal CORVET (C) and vacuolar HOPS complex (D) by affinity purification and gel filtration. (from Peplowska et al., 2007). Selected Publications 2004 - 2007 Karolina Peplowska, Daniel Markgraf, Clemens Ostrowicz, Gert Bange, and Christian Ungermann (2007) The CORVET tethering complex interacts with the Rab GTPase Vps21 (yeast Rab5) and is involved in endosome-vacuole biogenesis. Dev. Cell 12: 739-750. Martin Hofmann, Karolina Peplowska, Jan Rohde, Bernd Poschner, Christian Ungermann, and Dieter Langosch (2006). Self-interaction of a SNARE transmembrane domain promotes hemifusion-to-fusion transition. J. Mol. Biol. 346: 1048-1060 Kanagaraj Subramanian, Lars Dietrich, Haitong Hou, Tracy LaGrassa, Christoph Meiringer, and Christian Ungermann (2006). Palmitoylation determines the function of Vac8 at the yeast vacuole. J. Cell Sci. 119: 2477-2485. Christian Ungermann and Dieter Langosch (2005). Functions of SNAREs in intracellular membrane fusion and lipid bilayer mixing. J. Cell Sci. 118, 3819-3828 (Review) Tracy LaGrassa, and Christian Ungermann (2005) The vacuolar kinase Yck3 maintains organelle fragmentation by regulating the HOPS tethering complex. J. Cell Biol. 168: 401-14. Awards and Honors 2002 Member of the EMBO Young Investigator programme 2004 Heisenberg Stipend of the DFG 2004 Schering Habilitation price of the GBM Christian Ungermann new address since 2006: Professor of Biochemistry - Hans-Mühlenhoff Endowed Chair - University of Osnabrück Fachbereich Biologie Barbarastrasse 13 D-49076 Osnabrück Phone Office: +49-541-969-2752 Fax: +49 (0)541-969 2884 E-mail: Christian.Ungermann@biologie.uni-osnabrueck.de Homepage: http://www.biologie.uni-osnabrueck.de/ Biochemie/cu/index.html Christian Ungermann 37
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