Max Planck Institute for Molecular Physiology

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Max Planck Institute for
Molecular Physiology
Max Planck Institute for Molecular Physiology
MPI Dortmund
Category: research Institute
Carrier: Max Planck Society
Legal form of the carrier: Registered association
Seat of the wearer: Munich
Facility location: Dortmund
Type of research: Basic research
Subjects: Natural sciences
Areas of expertise: Cell biology , systems biology , structural biology , chemical biology
Basic funding: Federal government (50%), states (50%)
Employee: about 500
Homepage: www.mpi-dortmund.mpg.de

The Max Planck Institute (MPI) for Molecular Physiology is a research facility of the Max Planck Society based in Dortmund . The institute conducts basic biomedical research and pursues an interdisciplinary concept. Four scientific departments work at the interfaces between molecular cell biology , systems biology , structural biochemistry and chemical biology .

The research focus is on the holistic understanding of the mode of action of biomolecules and their dynamic interactions in the cell, and how these determine the properties and behavior of the cell and ultimately of a living system. Based on the elucidation of the structure of proteins and their complexes by means of high-resolution cryoelectron microscopy and X-ray crystallography , insights are gained on how intracellular processes such. B. the recognition and transmission of signals, take place at the molecular level. The identification and synthesis of small molecules close to natural substances enables the targeted modulation of biological processes and the tracking of complex signal pathways in the cell. To represent intracellular processes, which are determined in particular by the localization and interaction of proteins, modern fluorescence microscopic methods such. B. fluorescence lifetime microscopy (FLIM) is used. The interaction of the processes used in the four departments enables detailed insights into the highly dynamic signal transmission network of the cell and provides an understanding of the molecular causes of diseases such as cancer . An important aspect of research is influencing disease-causing processes with innovative active ingredients that serve as the basis for the development of novel therapeutic approaches. A potential approach for cancer therapy developed at the institute is based on modulating the location of the cancer protein Ras in the cell. Targeted manipulation of the transport of this signal protein using an inhibitor developed for this purpose at the institute made it possible to reduce the growth of cancer cells.

history

The Kaiser Wilhelm Institute for Occupational Physiology was founded in Berlin in 1913. The first director was Max Rubner. The institute was relocated to Dortmund in 1929 with a branch in Münster. Due to the war, the institute was relocated to Bad Ems and Diez an der Lahn in 1943. After the Second World War the institute was in Dortmund on the Rheinlanddamm.

In 1948, in the course of the transition from the Kaiser Wilhelm Society to the Max Planck Society, the institute was renamed the Max Planck Institute for Occupational Physiology. The Department of Nutritional Physiology was founded in 1956 as an independent MPI for Nutritional Physiology. The MPI for Occupational Physiology was renamed the MPI for Systems Physiology in 1973. The MPI for Nutritional Physiology and the MPI for Systems Physiology were merged to form the MPI for Molecular Physiology in 1993. In 1999 they moved into the new building on the campus of the University of Dortmund, today TU Dortmund .

Departments

Mechanistic cell biology

The Department of Mechanistic Cell Biology (Head: Andrea Musacchio ) deals with the molecular mechanisms of cell division and their regulation. The research focuses on proteins that control the process of chromosome separation during nuclear division ( mitosis ).

In the course of mitosis, the chromosomes, which consist of two identical sister chromatids, are separated from one another by the spindle apparatus. Two daughter kernels are created, each receiving one of the sister chromatids . The focus of the investigations is a complex network of interacting proteins and protein complexes that controls cell division and prevents incorrect distribution of the genetic material. Through structural and functional analyzes of the kinetochore , a protein complex that binds to the chromosomes, the research group was able to gain important knowledge about the regulation of the binding of the chromosomes to the spindle apparatus and contribute fundamental findings to the structure of the kinetochore. In addition, previously unknown interactions between the key proteins of an important control mechanism in mitosis, the “spindle assembly checkpoint” , could be detected.

Systemic cell biology

The research subject of the Department of Systemic Cell Biology (Head: Philippe Bastiaens) is the regulation of signal transmission processes in the cell, which determines important cellular functions such as the growth of tissue ( proliferation ) or the differentiation into different cell types and thus controls the fate of a cell.

The key to understanding these cellular decisions lies in the dynamic organization of signal proteins and their dynamic interactions in a signaling network. Disturbances in these networks are the cause of many diseases. You can e.g. B. cause unchecked proliferation of cells and lead to the development of cancer . Cancer research focuses on two key proteins , the small G protein Ras and the EGF receptor , which regulate both proliferation and differentiation in the MAP kinase signaling pathway . The researchers in the department were able to show that, regardless of the incoming signal, the same proteins are activated in the signal path, but remain activated for different lengths of time by switching negative or positive feedback mechanisms . In addition to the temporal variability of protein activity, the spatial distribution of proteins also plays a decisive role. Using fluorescence microscopic methods such as fluorescence lifetime microscopy (FLIM), the spatial enzymatic switch-off of signals could be visualized. Investigations into the localization of the cancer protein Ras, which is altered in every third tumor, revealed a previously unknown dynamic of this protein. The identification and characterization of an auxiliary protein, which is largely responsible for the transport and distribution of Ras in the cell, made it possible to develop a new, innovative approach in cancer therapy.

Structural biochemistry

The Department of Structural Biochemistry (Head: Stefan Raunser) focuses on structural and functional analyzes of biologically and medically relevant membrane proteins and macromolecular complexes. Research focuses on the investigation of the molecular mechanisms of muscle contraction and infection with bacterial toxins . Furthermore, membrane proteins are investigated, which play a key role in the synthesis, transport and homeostasis of cholesterol in the body.

Modern methods of electron microscopy and X-ray crystallography with a resolution in the atomic range are used to analyze protein structures . The use of cryoelectron microscopy , in which a sample is frozen to below 140 ° C in milliseconds, enables the structure analysis of a membrane protein in its almost native lipid environment. To do this, the sample is recorded under the microscope from different directions and reconstructed into a 3D data set. With this method it was possible for the first time to generate a high-resolution structure of F-actin , the main component of myofilaments in muscle cells , and of the entire actin - tropomyosin - myosin complex, which plays a central role in muscle contraction . These findings are of medical relevance, since mutations in the genes coding for actin can be the cause of numerous diseases of the muscles ( myopathies ) and blood vessels. Another research goal of the department is to elucidate the mechanisms used by bacteria to release toxins in the cells they have attacked. The scientists succeeded for the first time in the high-resolution representation of a bacterial protein complex that injects a deadly toxin into the cell with a syringe-like mechanism. Understanding the transport of bacterial agents can be e.g. B. be used for the development of biological pesticides . The bacterial protein complexes could also find application in medicine and be used for the application of active ingredients to e.g. B. To transport drugs precisely into cancer cells .

Chemical biology

The Department of Chemical Biology (Head: Herbert Waldmann ) conducts research at the interface between organic chemistry and biology . The focus of research is the identification and development of active substance-like, small molecules that are used as chemical tools for the investigation of biologically relevant processes. For this purpose, biochemical techniques as well as new methods and strategies in the organic synthesis of chemical compounds are developed.

Biologically active small molecules from nature serve as models for these low molecular weight compounds. Through evolutionary pressures, these molecules have developed important properties such as: B. a high affinity for proteins, and a high effectiveness on intra- and extracellular processes, such as signal transmission or the defense against organisms in the environment. Because of these properties, the chemical framework of natural products is an ideal starting point for the design and development of new biological active ingredients and for expanding substance libraries. On the basis of a new classification of the chemical framework of natural active ingredients and their extension to include synthetic substances with biological activity, an algorithm was developed in the department to reveal previously unknown classes of potentially active substances. Substances close to natural substances produced using innovative synthesis methods are first tested for their effectiveness in cell-based high - throughput processes and then the respective target protein is determined in subsequent processes such as affinity chromatography . Conversely, a specific inhibitor can also be identified on the basis of a known target protein . Such a target protein is, for example, the product of the oncogene RAS, which is mutated in every third tumor . The scientists succeeded in identifying and synthesizing a small molecule that suppresses the disease-causing effects of mutated Ras proteins by disrupting their transport within the cell.

Emeritus group

There are currently two emeritus groups at the institute. One is headed by Alfred Wittinghofer , who was director of the structural biology department at the institute from 1993 to 2009 and who is now an emeritus Scientific Member. Another group is led by Roger Goody , who was formerly director of the Physical Biochemistry Department.

Associated bodies

Chemical Genomics Center (CGC)

The Center for Chemical Genomics is a joint facility of the MPI for Molecular Physiology with several other Max Planck Institutes (coal research in Mülheim an der Ruhr , breeding research in Cologne, molecular cell biology and genetics in Dresden , psychiatry in Munich and biochemistry in Martinsried ). It is also supported by several companies hoping to gain new insights into drug strategies. Some of the working groups are located in the Biomedicine Center of the Dortmund Technology Park, which is right next to the MPI for Molecular Physiology .

Dortmund Protein Facility (DPF)

The Dortmund Protein Facility is a high throughput cloning and protein production unit for molecular physiology. It is intended to enable and promote the use of high throughput methods in molecular cloning , as well as in protein production and analysis.

Compound Management and Screening Center (COMAS)

The Compound Management and Screening Center, established in 2011 at the Dortmund MPI, has the task of bringing together the currently scattered substance libraries of the Max Planck Society and using them in a coordinated manner in biochemical and cellular screens. In an automatic −20 ° C substance store, chemical substances are stored under ideal conditions and prepared for distribution.

International Max Planck Research School in Chemical Biology (IMPRS)

In cooperation with the universities in Dortmund and Bochum , the MPI offers graduate studies in chemical biology within the framework of an International Max Planck Research School (IMPRS), which leads to a doctorate in natural sciences or a doctorate in philosophy, analogous to the English Ph. D. . leads. The training takes place in English, not least because the target group is primarily foreign students who are doing their doctorate in Germany in this way. Since the Max Planck Institute itself is not entitled to award a doctorate, the doctorate is carried out at one of the participating universities according to their doctoral regulations. The IMPRS issues a confirmation of the additional qualifications. The lectures attended as part of the IMPRS are recognized by the participating universities for the doctoral requirements. Only some of the institute's doctoral students are doing their doctorates within the framework of the IMPRS.

literature

  • Adolf von Harnack : Speeches at the inauguration of the new building of the Kaiser Wilhelm Institute for Occupational Physiology. (1929), In: Bernhard Fabian (Ed.): Adolf von Harnack - Speeches and essays on science policy. Olms-Weidmann, Hildesheim / Zurich / New York 2001, ISBN 3-487-11369-4 , pp. 71-74.
  • Theo Plesser, Hans-Ulrich Thamer (Ed.): Work, performance and nutrition: from the Kaiser Wilhelm Institute for Work Physiology in Berlin to the Max Planck Institute for Molecular Physiology and Leibniz Institute for Labor Research in Dortmund. (= Pallas Athene. Volume 44). Steiner, Stuttgart 2012, ISBN 978-3-515-10200-1 .
  • Max Planck Institute for Molecular Physiology. In: Peter Gruss , Reinhard Rürup , Susanne Kiewitz (eds.): Denkorte. Sandstein Verlag, Dresden 2010, ISBN 978-3-942422-01-7 , pp. 276-291.

Web links

Individual evidence

  1. ↑ a b mpg.de
  2. ↑ a b c G. Zimmerman, B. Papke, S. Ismail, N. Vartak, A. Chandra, M. Hoffmann, SA Hahn, G. Triola, A. Wittinghofer, PI Bastiaens, H. Waldmann: Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signaling. In: Nature. 497 (7451), May 30, 2013, pp. 638-642. doi: 10.1038 / nature12205 . Epub 2013 May 22. PMID 23698361
  3. ↑ A. Petrovic, S. Mosalaganti, J. Keller, M. Mattiuzzo, K. Overlack, V. Krenn, A. De Antoni, S. Wohlgemuth, V. Cecatiello, S. Pasqualato, S. Raunser, A. Musacchio: Modular Assembly of RWD Domains on the Mis12 Complex Underlies Outer Kinetochore Organization. In: Mol Cell. 53, 2014, pp. 591-605. PMID 24530301
  4. ↑ F. Basilico, S. Maffini, JR Weir, D. Prumbaum, AM Rojas, T. Zimniak, A. De Antoni, S. Jeganathan, B. Voss, S. van Gerwen, V. Krenn, L. Massimiliano, A Valencia, IR Vetter, F. Herzog, S. Raunser, S. Pasqualato, A. Musacchio: The pseudo GTPase CENP-M drives human kinetochore assembly. In: Elife. 3, 2014, p. E02978. doi: 10.7554 / eLife.02978 . PMID 25006165
  5. ^ I. Primorac, JR Weir, E. Chiroli, F. Gross, I. Hoffmann, S. van Gerwen, A. Ciliberto, A. Musacchio: Bub3 reads phosphorylated MELT repeats to promote spindle assembly checkpoint signaling. In: Elife. 2, 2013, p. E01030. doi: 10.7554 / eLife.01030 . PMID 24066227
  6. ↑ K. Overlack, I. Primorac, M. Vleugel, V. Krenn, S. Maffini, I. Hoffmann, GJ Kops, A. Musacchio: A molecular basis for the differential roles of Bub1 and BubR1 in the spindle assembly checkpoint. In: Elife. 4, 2015, p. E05269. doi: 10.7554 / eLife.05269 . PMID 25611342
  7. ^ S. Santos, P. Verveer, PI Bastiaens: Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate. In: Nat Cell Biol. 9 (3), 2007, pp. 324-330. PMID 17310240
  8. ↑ IA Yudushkin, A. Schleifenbaum, A. Kinkhabwala, BG Neel, C. Schultz, PI Bastiaens: Live Cell Imaging of Enzyme substrates Interaction Reveals Spatial Regulation of PTP1B. In: Science. 315 (5808), 2007, pp. 115-119. PMID 17204654
  9. ↑ O. Rocks, A. Peyker, M. Kahms, PJ Verveer, C. Koerner, M. Lumbierres, J. Kuhlmann, H. Waldmann, A. Wittinghofer, PI Bastiaens: An acylation cycle regulates localization and activity of palmitoylated Ras isoforms . In: Science. 307, 2005, pp. 1746-1752. PMID 15705808
  10. ↑ M. Schmick, p Vartak, B. Papke, M. Kovacevic, D. Truxius, L. Rossmannek, PI Bastiaens: KRAS localizes to the plasma membrane by Spatial Cycles of solubilization, trapping and vesicular transport. In: Cell. 157 (2), 2014, pp. 459-471. PMID 24725411
  11. ↑ A. Chandra, H. Grecco, V. Pisupati, D. Perera, L. Cassidy, F. Skoulidis, S. Ismail, C. Hedberg, M. Hanzal-Bayer, A. Venkitaraman, A. Wittinghofer, PI Bastiaens: The GDI-like solubilizing factor PDEδ sustains the spatial organization and signaling of Ras family proteins. In: Nat Cell Biol. 14, 2011, pp. 1-13. PMID 22179043
  12. ^ E. Behrmann, M. Müller, PA Penczek, HG Mannherz, DJ Manstein, S. Raunser: Structure of the rigor actin-tropomyosin complex. In: Cell. 150 (2), 2012, pp. 327-338. PMID 22817895
  13. ↑ J. von der Ecken, M. Müller, W. Lehman, DJ Manstein, PA Penczek, S. Raunser: Structure of the F-actin-tropomyosin complex. In: Nature. 519 (7541), 2015, pp. 114-117 (2015) PMID 25470062
  14. ↑ J. von der Ecken, SM Heissler, S. Pathan-Chhatbar, DJ Manstein, S. Raunser: Cryo-EM structure of a human cytoplasmic actomyosin complex at near-atomic resolution. In: Nature. 534 (7609), 2016, pp. 724-728 (2016) PMID 27324845
  15. ↑ C. Gatsogiannis, AE Lang, D. Meusch, V. Pfaumann, O. Hofnagel, R. Benz, K. Aktories, S. Raunser: A syringe-like injection mechanism on Photorhabdus luminescens toxins. In: Nature. 495 (7442), 2013, pp. 520-523. PMID 23515159
  16. ↑ D. Meusch, C. Gatsogiannis, RG Efremov, AE Lang, O. Hofnagel, IR Vetter, K. Aktories, S. Raunser: Mechanism of Tc toxin action revealed in molecular detail. In: Nature. 508 (7494), 2014, pp. 61-65. PMID 24572368
  17. ↑ laborundmore.com
  18. Jump up ↑ MA Koch, A. Schuffenhauer, M. Scheck, S. Wetzel, M. Casaulta, A. Odermatt, O. Ertl, H. Waldmann: Charting biologically relevant chemical space: a structural classification of natural products (SCONP). In: Proc Natl Acad Sci USA. 102 (48), 2005, pp. 17272-17277. PMID 16301544
  19. ↑ RS Bon, H. Waldmann: Bioactivity-guided navigation of chemical space. In: Acc Chem Res. 43 (8), 2010, pp. 1103-1114. PMID 20481515
  20. ^ S. Wetzel, K. Klein, S. Renner, D. Rauh, TI Oprea, P. Mutzel, H. Waldmann: Interactive exploration of chemical space with Scaffold Hunter. In: Nat Chem Biol. 5 (8), 2009, pp. 581-583. PMID 19561620
  21. ↑ A. Ursu, H. Waldmann: Hide and seek: Identification and confirmation of small molecule protein targets. In: Bioorg Med Chem Lett. 25 (16), 2015, pp. 3079-3086. PMID 26115575
  22. ↑ S. Ziegler, V. Pries, C. Hedberg, H. Waldmann: Target identification for small bioactive molecules: finding the needle in the haystack. In: Angew Chem Int Ed Engl. 52 (10), 2013, pp. 2744-2792. PMID 23418026
  23. ↑ see homepage of the IMPRS International Max Planck Research School in Chemical and Molecular Biology , accessed on June 23, 2016.

Coordinates: 51 ° 29 ′ 22.8 "  N , 7 ° 24 ′ 35.3"  E