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Structural Biology of Mitochondrial Outer Membrane Proteins
Third-party funded project
Project title Structural Biology of Mitochondrial Outer Membrane Proteins
Principal Investigator(s) Hiller, Sebastian
Project Members Reckel, Sina
Diogo Adaixo, Ricardo Jorge
Böhm, Raphael
Aragao Correia, Hugo
Burmann, Irena
Zahn, Michael
Organisation / Research unit Departement Biozentrum / Structural Biology (Hiller)
Project start 01.12.2011
Probable end 30.11.2016
Status Completed
Abstract

To elucidate the biological role of the mitochondrial outer membrane (MOM), we want to determine structures and functions of integral MOM protein complexes at atomic resolution, involving the three proteins VDAC, Bax and Sam. These are key elements of vital cellular functions: the regulation of bioenergetics, mitochondrial biogenesis, apoptosis and cancer. Our results will give new insights into the biology of eukaryotes and may open up new avenues for pharmaceutical applications. We want to pursue the following objectives:

A. Determination of the structures of the VDAC–NADH, the VDAC–cholesterol, and the VDAC–hexokinase complexes. These structures will provide the molecular basis for metabolism regulation by the voltage-dependent anion channel VDAC and for its role in the “Warburg effect”, a crucial step of cancerogenesis of most cancers.

B. Determination of the structure and insertion mechanism of the Bax transmembrane-pore and its formation and inhibition by drug candidates. The formation of the Bax pore in the MOM is the final, deadly step in mitochondrial apoptosis and the structure will thus elucidate a key regulatory element of multicellular organisms.

C. Determination of the structure and function of the sorting and assembly machinery (Sam), including its core protein, the beta-barrel protein Sam50, and its interactions with substrates. These results will explain the insertion of membrane proteins during the biogenesis of the MOM, an essential for eukaryotic life.

Structure determinations of membrane proteins are still major technical challenges and so far, with VDAC, only a single structure of an integral MOM protein is known, determined by the present author and colleagues. While bringing groundbreaking biological insights, our research will further extend the methodological approaches for membrane protein structure determination by nuclear magnetic resonance (NMR) spectroscopy to a new level.

Keywords NMR spectroscopy, membrane protein, protein folding, apoptosis, mitochondria, cancer
Financed by Commission of the European Union

Published results ()

  ID Autor(en) Titel ISSN / ISBN Erschienen in Art der Publikation
1171037  Yu, Tsyr-Yan; Raschle, Thomas; Hiller, Sebastian; Wagner, Gerhard  Solution NMR spectroscopic characterization of human VDAC-2 in detergent micelles and lipid bilayer nanodiscs  0006-3002  Biochimica et biophysica acta. BBA. Biomembranes  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
1171039  Hiller, Sebastian; Wagner, Gerhard  Solution NMR Spectroscopy of Integral Membrane Proteins  978-0-444-56342-2  Comprehensive Biophysics  Publication: Book Item (Buchkap., Lexikonartikel, jur. Kommentierung, Beiträge in Sammelbänden etc.) 
1335462  Harsman, Anke; Niemann, Moritz; Pusnik, Mascha; Schmidt, Oliver; Burmann, Björn M.; Hiller, Sebastian; Meisinger, Chris; Schneider, André; Wagner, Richard  Bacterial origin of a mitochondrial outer membrane protein translocase : new perspectives from comparative single channel electrophysiology  0021-9258  Journal of biological chemistry  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
2102027  Reckel, Sina; Hiller, Sebastian  Perspectives of Solution NMR Spectroscopy for Structural and Functional Studies of Integral Membrane Proteins  0026-8976  Molecular physics  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
2158966  Hiller, Sebastian  The functional heart of the M2 channel  0006-3495  Biophysical journal  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
2158967  Burmann, Björn M.; Hiller, Sebastian  Solution NMR studies of membrane-protein-chaperone complexes  0009-4293  Chimia  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
2238353  Gruss, Fabian; Zähringer, Franziska; Jakob, Roman P.; Burmann, Björn M.; Hiller, Sebastian; Maier, Timm  The structural basis of autotransporter translocation by TamA  1545-9993  Nature structural & molecular biology  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
2291402  Burmann, Björn M.; Wang, Congwei; Hiller, Sebastian  Conformation and dynamics of the periplasmic membrane-protein–chaperone complexes OmpX–Skp and tOmpA–Skp  1545-9993  Nature structural & molecular biology  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
2291403  Gruss, F.; Zähringer, F.; Jakob, R.P.; Burmann, B.M.; Hiller, S.; Maier, T.  The structural basis of autotransporter translocation by TamA.  1545-9985  Nat. Struct. Mol. Biol.  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
2609334  Schnarwiler, Felix; Niemann, Moritz; Doiron, Nicholas; Harsman, Anke; Käser, Sandro; Mani, Jan; Chanfon, Astrid; Dewar, Caroline E.; Oeljeklaus, Silke; Jackson, Christopher B.; Pusnik, Mascha; Schmidt, Oliver; Meisinger, Chris; Hiller, Sebastian; Warscheid, Bettina; Schnaufer, Achim C.; Ochsenreiter, Torsten; Schneider, André  Trypanosomal TAC40 constitutes a novel subclass of mitochondrial β-barrel proteins specialized in mitochondrial genome inheritance  0027-8424  Proceedings of the National Academy of Sciences of the United States of America  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
2609335  Callon, Morgane; Burmann, Björn M.; Hiller, Sebastian  Structural mapping of a chaperone-substrate interaction surface  1521-3773  Angewandte Chemie. International edition in English  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
2609336  Etzkorn, Manuela; Zoonens, Manuel; Catoire, Laurent J.; Popot, Jean-Luc; Hiller, Sebastian  How amphipols embed membrane proteins : global solvent accessibility and interaction with a flexible protein terminus  0022-2631  The journal of membrane biology  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
2814836  Jakob, Roman P.; Koch, Johanna R.; Burmann, Björn M.; Schmidpeter, Philipp A. M.; Hunkeler, Moritz; Hiller, Sebastian; Schmid, Franz X.; Maier, Timm  Dimeric structure of the bacterial extracellular foldase PrsA  0021-9258 ; 1083-351X  Journal of Biological Chemistry  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
2859572  Morgado, Leonor; Zeth, Kornelius; Burmann, Björn M.; Maier, Timm; Hiller, Sebastian  Characterization of the insertase BamA in three different membrane mimetics by solution NMR spectroscopy  0925-2738  Journal of biomolecular NMR  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
3135946  Maier, Timm; Clantin, Bernard; Gruss, Fabian; Dewitte, Frédérique; Delattre, Anne-Sophie; Jacob-Dubuisson, Françoise; Hiller, Sebastian; Villeret, Vincent  Conserved Omp85 lid-lock structure and substrate recognition in FhaC  2041-1723  Nature Communications  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
3137438  Brahimi-Horn, M. Christiane; Lacas-Gervais, Sandra; Adaixo, Ricardo; Ilc, Karine; Rouleau, Matthieu; Notte, Annick; Dieu, Marc; Michiels, Carine; Voeltzel, Thibault; Maguer-Satta, Véronique; Pelletier, Joffrey; Ilie, Marius; Hofman, Paul; Manoury, Bénédicte; Schmidt, Alexander; Hiller, Sebastian; Pouysségur, Jacques; Mazure, Natalie M.  Local mitochondrial-endolysosomal microfusion cleaves voltage-dependent anion channel 1 to promote survival in hypoxia  1098-5549  Molecular and cellular biology  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
3137439  Morgado, L.; Zeth, K.; Burmann, B.M.; Maier, T.; Hiller, S.  Characterization of the insertase BamA in three different membrane mimetics by solution NMR spectroscopy.  1573-5001  J. Biomol. NMR  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
3210555  Thoma, Johannes; Burmann, Björn M.; Hiller, Sebastian; Müller, Daniel J.  Impact of holdase chaperones Skp and SurA on the folding of β-barrel outer-membrane proteins  1545-9993  Nature structural & molecular biology  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
3245159  Gruss, Fabian; Hiller, Sebastian; Maier, Timm  Purification and Bicelle Crystallization for Structure Determination of the E. coli Outer Membrane Protein TamA  1064-3745 ; 1940-6029  Methods in Molecular Biology  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
3395112  Burmann, Björn M.; Hiller, Sebastian  Chaperones and chaperone-substrate complexes: dynamic playgrounds for NMR spectroscopists  0079-6565  Progress in Nuclear Magnetic Resonance Spectroscopy  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
3511269  Raschle, Thomas; Rios Flores, Perla; Opitz, Christian; Müller, Daniel J.; Hiller, Sebastian  Monitoring Backbone Hydrogen-Bond Formation in β-Barrel Membrane Protein Folding  1521-3773  Angewandte Chemie. International edition in English  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 

Cooperations ()

  ID Kreditinhaber Kooperationspartner Institution Laufzeit - von Laufzeit - bis
471418  Hiller, Sebastian  Wagner, Gerhard, Prof.  Harvard Medical School  01.08.2010  01.12.2016 
998004  Hiller, Sebastian  Stahlberg, Henning, Prof.  Biozentrum Basel  01.12.2011  01.12.2016 
998011  Hiller, Sebastian  Meier, Beat, Prof.  ETH Zurich  01.12.2011  01.12.2016 
   

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