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Agarwal, R., and Duderstadt, K.E.
Nat Commun, 2020, 11, 4714.
doi: 10.1038/s41467-020-18456-y

Multiplex flow magnetic tweezers reveal rare enzymatic events with single molecule precision

The application of forces and torques on the single molecule level has transformed our understanding of the dynamic properties of biomolecules, but rare intermediates have remained difficult to characterize due to limited throughput. Here, we describe a method that provides a 100-fold improvement in the throughput of force spectroscopy measurements with topological control, which enables routine imaging of 50,000 single molecules and a 100 million reaction cycles in parallel. This improvement enables detection of rare events in the life cycle of the cell. As a demonstration, we characterize the supercoiling dynamics and drug-induced DNA break intermediates of topoisomerases. To rapidly quantify distinct classes of dynamic behaviors and rare events, we developed a software platform with an automated feature classification pipeline. The method and software can be readily adapted for studies of a broad range of complex, multistep enzymatic pathways in which rare intermediates have escaped classification due to limited throughput.

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Gehrlach, D.A., Weiand, C., Gaitanos, T.N., Cho, E., Klein, A.S., Hennrich, A.A., Conzelmann, K.K., and Gogolla, N. (IMPRS-LS students are in bold)
Elife, 2020, 9.
doi: 10.7554/eLife.55585

A whole-brain connectivity map of mouse insular cortex

The insular cortex (IC) plays key roles in emotional and regulatory brain functions and is affected across psychiatric diseases. However, the brain-wide connections of the mouse IC have not been comprehensively mapped. Here, we traced the whole-brain inputs and outputs of the mouse IC across its rostro-caudal extent. We employed cell-type-specific monosynaptic rabies virus tracings to characterize afferent connections onto either excitatory or inhibitory IC neurons, and adeno-associated viral tracings to label excitatory efferent axons. While the connectivity between the IC and other cortical regions was highly bidirectional, the IC connectivity with subcortical structures was often unidirectional, revealing prominent cortical-to-subcortical or subcortical-to-cortical pathways. The posterior and medial IC exhibited resembling connectivity patterns, while the anterior IC connectivity was distinct, suggesting two major functional compartments. Our results provide insights into the anatomical architecture of the mouse IC and thus a structural basis to guide investigations into its complex functions.

Support for the new Max Planck life science campus in Martinsried and the initiative for quantum computing and quantum technologies

Mastering transformation with technology – that is the motto of the Bavarian State Government, whose Hightech Agenda saw Bavaria launch Germany’s only technology offensive of its kind a year ago. With an injection of EUR 2 billion, 1,000 new professorships and 13,000 new university places, the Free State of Bavaria wants to build upon its leading position in research. The Max-Planck-Gesellschaft welcomes the fact that, with the latest cabinet decision of 14 September 2020, significant additional funding is being committed to cutting-edge research, including at Max Planck Institutes. At a press conference, Bavarian Prime Minister Markus Söder raised the prospect of significant support for the establishment of a life science campus in Martinsried for interdisciplinary and interactive research in the biosciences. On the Martinsried campus, the Max-Planck-Gesellschaft plans to establish a new Max Planck Institute for the Study of Life with a view to pooling and realigning its existing strengths. With an equivalent of 18 Departments, the Institute will be the largest of the Max Planck Institutes and will initially focus on the synthesis of artificial cells and the study of the brain in its natural environment (real-life neuroscience).

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Peter Krenn from the Department Molecular Medicine (Director Reinhard Fässler) at the Max Planck Institute of Biochemistry has found a new way to attack leukemic stem cells.

Blood – the juice of life Blood supplies complex organisms with nutritive substances, transports metabolic products or messenger substances. Cellular components of blood are erythrocytes responsible for the transport of oxygen and carbon dioxide, thrombocytes responsible for blood coagulation and leukocytes responsible for the immune defense. As each of these blood cells has a limited lifespan, and are massively lost during bleeding or consumed during infections. Hence, they must be continuously replaced, which is ensured by the so-called hematopoietic stem cells in the bone marrow. These cells have the ability to develop into any type of blood cell. Chronic myeloid leukemia In chronic myeloid leukemia, the hematopoietic stem cell undergoes a genetic mutation by recombining chromosome 9 and 22. As a result, gene building blocks fuse that would otherwise not be in contact with each other. The incorrectly assembled chromosome is called Philadelphia chromosome and harbors the construction manual for the so-called BCR-ABL oncogene. This causes the leukemic stem cell to behave selfishly: it divides and multiplies drastically at the expense of healthy blood stem cells.

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graduationCongratulations on your PhD!

Daniel Gehrlach
Anatomical and functional characterization of the mouse insular cortex
RG: Nadine Gogolla

Daniil Markov
Involvement of cerebellar Purkinje cells in adaptive locomotion of larval zebrafish
RG: Ruben Portugues


MPIB scientists have contributed to deciphering the 3D structure of the nuclear pore of baker's yeast cells.

Research group leader Boris Pfander and his team from the Max Planck Institute of Biochemistry, together with colleagues from the Max Planck Institute of Biophysics in Frankfurt am Main and the EMBL in Heidelberg, have investigated the 3D structure of nuclear pores in budding yeast (Saccharomyces cerevisiae). Their results, published in Nature, reveal the architecture of the nuclear pore complex in intact cells and broaden our understanding of crucial processes in life.

Nuclear pores are a highly complex assembly of proteins. Hundreds of them are embedded in the double membrane that surrounds and protects the cell’s nucleus. They act as a gateway that regulates the entry and exit of molecules. An important function of nuclear pores is to regulate the export of a molecule called messenger RNA (mRNA) from the nucleus into the surrounding cell – the cytoplasm – where it delivers instructions for the assembly of proteins. Revealing the architecture Now the scientists appreciate better how the nuclear pore works in its native context, how it is maintained and recycled. The study provides a detailed structural description of the three protein rings that make up the nuclear pore, known as the cytoplasmic, nuclear, and inner rings. To show how these rings are arranged in cells, the researchers used a combination of cell biology, computational modelling, and in-cell cryo-electron tomography: an imaging technique, that is used to produce high-resolution 3D views of the molecular landscape inside a cell. This led to fundamental new insights. The scientist found out that the 3D configuration of the cytoplasmic ring accommodates the path of mRNA export.

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Eklund, A.S., Ganji, M., Gavins, G., Seitz, O., and Jungmann, R.
Nano Lett, 2020, [Epub ahead of print].
doi: 10.1021/acs.nanolett.0c02620

Peptide-PAINT Super-Resolution Imaging Using Transient Coiled Coil Interactions

Super-resolution microscopy is transforming research in the life sciences by enabling the visualization of structures and interactions on the nanoscale. DNA-PAINT is a relatively easy-to-implement single-molecule-based technique, which uses the programmable and transient interaction of dye-labeled oligonucleotides with their complements for super-resolution imaging. However, similar to many imaging approaches, it is still hampered by the subpar performance of labeling probes in terms of their large size and limited labeling efficiency. To overcome this, we here translate the programmability and transient binding nature of DNA-PAINT to coiled coil interactions of short peptides and introduce Peptide-PAINT. We benchmark and optimize its binding kinetics in a single-molecule assay and demonstrate its super-resolution capability using self-assembled DNA origami structures. Peptide-PAINT outperforms classical DNA-PAINT in terms of imaging speed and efficiency. Finally, we prove the suitability of Peptide-PAINT for cellular super-resolution imaging by visualizing the microtubule and vimentin network in fixed cells.

Ralf Jungmann, Research Group Leader at the Max Planck Institute (MPI) of Biochemistry and Professor for Experimental Physics at the LMU Munich, together with Maartje Bastings, Director of the Programmable Biomaterials Laboratory (PBL) in the EPFL School of Engineering (STI), and Ian Parish from the University of Melbourne and Peter MacCallum Cancer Centre in Melbourne, have received 1.5 million euros in research funding from the Volkswagen Foundation. The joint project of the three research groups, funded through the initiative ”Life? – A Fresh Scientific Approach to the Basic Principles of Life” from the Volkswagen Foundation, is aimed at unraveling the origin of multicellular life. The evolution of complex multicellular organisms 600 million years ago required sophisticated cell-cell communication systems to coordinate growth, differentiation, and tissue organization. This evolutionary leap is thought to have required a fundamental change in protein organization at the key interface for intercellular communication: the cell surface.

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graduationCongratulations on your PhD!

Jennifer Wells
Structural and Functional Analysis of Transitionally Inactive Eukaryotic Ribosomes:
Regulation of Hibernation with Lso2/CCDC124 and Stalling on the Fungal Arginine
Attenuator Peptide
RG: Roland Beckmann



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Varga, J., Nicolas, A., Petrocelli, V., Pesic, M., Mahmoud, A., Michels, B.E., Etlioglu, E., Yepes, D., Häupl, B., Ziegler, P.K., Bankov, K., Wild, P.J., Wanninger, S., Medyouf, H., Farin, H.F., Tejpar, S., Oellerich, T., Ruland, J., Siebel, C.W., and Greten, F.R.
J Exp Med, 2020, 217.
doi: 10.1084/jem.20191515

AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer

Recently, a transcriptome-based consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established, which may ultimately help to individualize CRC therapy. However, the lack of animal models that faithfully recapitulate the different molecular subtypes impedes adequate preclinical testing of stratified therapeutic concepts. Here, we demonstrate that constitutive AKT activation in intestinal epithelial cells markedly enhances tumor invasion and metastasis in Trp53ΔIEC mice (Trp53ΔIECAktE17K) upon challenge with the carcinogen azoxymethane. Gene-expression profiling indicates that Trp53ΔIECAktE17K tumors resemble the human mesenchymal colorectal cancer subtype (CMS4), which is characterized by the poorest survival rate among the four CMSs. Trp53ΔIECAktE17K tumor cells are characterized by Notch3 up-regulation, and treatment of Trp53ΔIECAktE17K mice with a NOTCH3-inhibiting antibody reduces invasion and metastasis. In CRC patients, NOTCH3 expression correlates positively with tumor grading and the presence of lymph node as well as distant metastases and is specifically up-regulated in CMS4 tumors. Therefore, we suggest NOTCH3 as a putative target for advanced CMS4 CRC patients.