F. Ulrich Hartl, Director at the Max Planck Institute of Biochemistry in Martinsried was awarded the Bavarian Maximilian Order for Science and Art.

F. Ulrich Hartl, director of the research department "Cellular Biochemistry" at the Max Planck Institute of Biochemistry in Martinsried, received the Bavarian Order of Maximilian in the Munich Residence on November 10. With this award, the Free State of Bavaria honors the highest scientific and artistic achievements. F. Ulrich Hartl investigates how proteins fold properly and what role misfolded structures and protein aggregates play in aging and neurodegenerative diseases such as Alzheimer's and Parkinson's: "I feel very honored to receive this recognition." In addition to Hartl, nine other personalities received the award this year, including the president of the Max Planck Society, Martin Stratmann.

Proteins can only fulfill their complex tasks in the organism if they are folded correctly. However, correct folding often requires helper proteins, the so-called molecular chaperones. The researchers led by F. Ulrich Hartl are investigating the structure and function of these molecules. For the "chaperonin" subgroup, the scientists have already been able to show in detail how they work: They encapsulate proteins during their folding so that aggregates cannot form. Such aggregates can be the cause of neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease. F. Ulrich Hartl and his team are also searching for strategies to prevent proteins from forming aggregates, which one day might become useful in treating these presently incurable diseases. 

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Holtkamp, S.J., Ince, L.M., Barnoud, C., Schmitt, M.T., Sinturel, F., Pilorz, V., Pick, R., Jemelin, S., Mühlstädt, M., Boehncke, W.H., Weber, J., Laubender, D., Philippou-Massier, J., Chen, C.S., Holtermann, L., Vestweber, D., Sperandio, M., Schraml, B.U., Halin, C., Dibner, C., Oster, H., Renkawitz, J., and Scheiermann, C.
(IMPRS-LS students are in bold)
Nat Immunol, 2021, 22, 1375-1381.
doi: 10.1038/s41590-021-01040-x

Circadian clocks guide dendritic cells into skin lymphatics

Migration of leukocytes from the skin to lymph nodes (LNs) via afferent lymphatic vessels (LVs) is pivotal for adaptive immune responses1,2. Circadian rhythms have emerged as important regulators of leukocyte trafficking to LNs via the blood3,4. Here, we demonstrate that dendritic cells (DCs) have a circadian migration pattern into LVs, which peaks during the rest phase in mice. This migration pattern is determined by rhythmic gradients in the expression of the chemokine CCL21 and of adhesion molecules in both mice and humans. Chronopharmacological targeting of the involved factors abrogates circadian migration of DCs. We identify cell-intrinsic circadian oscillations in skin lymphatic endothelial cells (LECs) and DCs that cogovern these rhythms, as their genetic disruption in either cell type ablates circadian trafficking. These observations indicate that circadian clocks control the infiltration of DCs into skin lymphatics, a process that is essential for many adaptive immune responses and relevant for vaccination and immunotherapies.




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Johanna Brüggenthies

Genetic and chemical perturbation of amino acid sening by the GCN1-GCN2 pathway

RG: Peter Murray



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Kostrhon, S., Prabu, J.R., Baek, K., Horn-Ghetko, D., von Gronau, S., Klügel, M., Basquin, J., Alpi, A.F., and Schulman, B.A.
(IMPRS-LS students are in bold)
Nat Chem Biol, 2021, 17, 1075-1083.
doi: 10.1038/s41589-021-00858-8

CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation

An emerging mechanism of ubiquitylation involves partnering of two distinct E3 ligases. In the best-characterized E3-E3 pathways, ARIH-family RING-between-RING (RBR) E3s ligate ubiquitin to substrates of neddylated cullin-RING E3s. The E3 ARIH2 has been implicated in ubiquitylation of substrates of neddylated CUL5-RBX2-based E3s, including APOBEC3-family substrates of the host E3 hijacked by HIV-1 virion infectivity factor (Vif). However, the structural mechanisms remained elusive. Here structural and biochemical analyses reveal distinctive ARIH2 autoinhibition, and activation on assembly with neddylated CUL5-RBX2. Comparison to structures of E3-E3 assemblies comprising ARIH1 and neddylated CUL1-RBX1-based E3s shows cullin-specific regulation by NEDD8. Whereas CUL1-linked NEDD8 directly recruits ARIH1, CUL5-linked NEDD8 does not bind ARIH2. Instead, the data reveal an allosteric mechanism. NEDD8 uniquely contacts covalently linked CUL5, and elicits structural rearrangements that unveil cryptic ARIH2-binding sites. The data reveal how a ubiquitin-like protein induces protein-protein interactions indirectly, through allostery. Allosteric specificity of ubiquitin-like protein modifications may offer opportunities for therapeutic targeting.



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Eklund, A.S., Comberlato, A., Parish, I.A., Jungmann, R., and Bastings, M.M.C.
ACS Nano, 2021, online ahead of print.
doi: 10.1021/acsnano.1c05540

Quantification of Strand Accessibility in Biostable DNA Origami with Single-Staple Resolution

DNA-based nanostructures are actively gaining interest as tools for biomedical and therapeutic applications following the recent development of protective coating strategies prolonging structural integrity in physiological conditions. For tailored biological action, these nanostructures are often functionalized with targeting or imaging labels using DNA base pairing. Only if these labels are accessible on the structure's surface will they be able to interact with their intended biological target. However, the accessibility of functional sites for different geometries and environments, specifically after the application of a protective coating, is currently not known. Here, we assay this accessibility on the level of single handle strands with two- and three-dimensional resolution using DNA-PAINT and show that the hybridization kinetics of top and bottom sides on the same nanostructure linked to a surface remain unaltered. We furthermore demonstrate that the functionality of the structures remains available after an oligolysine-PEG coating is applied, enabling bioassays where functionality and stability are imperative.




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Ksenia Finogenova

Structural basis of nucleosome binding by PRC2 and its regulation by histone modifications

RG: Jürg Müller



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Tüshaus, J., Kataka, E.S., Zaucha, J., Frishman, D., Müller, S.A., and Lichtenthaler, S.F.
Proteomics, 2021, 21, e2000174.
doi: 10.1002/pmic.202000174

Neuronal Differentiation of LUHMES Cells Induces Substantial Changes of the Proteome

Neuronal cell lines are important model systems to study mechanisms of neurodegenerative diseases. One example is the Lund Human Mesencephalic (LUHMES) cell line, which can differentiate into dopaminergic-like neurons and is frequently used to study mechanisms of Parkinson's disease and neurotoxicity. Neuronal differentiation of LUHMES cells is commonly verified with selected neuronal markers, but little is known about the proteome-wide protein abundance changes during differentiation. Using mass spectrometry and label-free quantification (LFQ), the proteome of differentiated and undifferentiated LUHMES cells and of primary murine midbrain neurons are compared. Neuronal differentiation induced substantial changes of the LUHMES cell proteome, with proliferation-related proteins being strongly down-regulated and neuronal and dopaminergic proteins, such as L1CAM and α-synuclein (SNCA) being up to 1,000-fold up-regulated. Several of these proteins, including MAPT and SYN1, may be useful as new markers for experimentally validating neuronal differentiation of LUHMES cells. Primary midbrain neurons are slightly more closely related to differentiated than to undifferentiated LUHMES cells, in particular with respect to the abundance of proteins related to neurodegeneration. In summary, the analysis demonstrates that differentiated LUHMES cells are a suitable model for studies on neurodegeneration and provides a resource of the proteome-wide changes during neuronal differentiation. (ProteomeXchange identifier PXD020044).



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Tüshaus, J., Müller, S.A., Shrouder, J., Arends, M., Simons, M., Plesnila, N., Blobel, C.P., and Lichtenthaler, S.F
FASEB J, 2021, 35, e21962
doi: 10.1096/fj.202100936R

The pseudoprotease iRhom1 controls ectodomain shedding of membrane proteins in the nervous system

Proteolytic ectodomain shedding of membrane proteins is a fundamental mechanism to control the communication between cells and their environment. A key protease for membrane protein shedding is ADAM17, which requires a non-proteolytic subunit, either inactive Rhomboid 1 (iRhom1) or iRhom2 for its activity. While iRhom1 and iRhom2 are co-expressed in most tissues and appear to have largely redundant functions, the brain is an organ with predominant expression of iRhom1. Yet, little is known about the spatio-temporal expression of iRhom1 in mammalian brain and about its function in controlling membrane protein shedding in the nervous system. Here, we demonstrate that iRhom1 is expressed in mouse brain from the prenatal stage to adulthood with a peak in early postnatal development. In the adult mouse brain iRhom1 was widely expressed, including in cortex, hippocampus, olfactory bulb, and cerebellum. Proteomic analysis of the secretome of primary neurons using the hiSPECS method and of cerebrospinal fluid, obtained from iRhom1-deficient and control mice, identified several membrane proteins that require iRhom1 for their shedding in vitro or in vivo. One of these proteins was 'multiple-EGF-like-domains protein 10' (MEGF10), a phagocytic receptor in the brain that is linked to the removal of amyloid β and apoptotic neurons. MEGF10 was further validated as an ADAM17 substrate using ADAM17-deficient mouse embryonic fibroblasts. Taken together, this study discovers a role for iRhom1 in controlling membrane protein shedding in the mouse brain, establishes MEGF10 as an iRhom1-dependent ADAM17 substrate and demonstrates that iRhom1 is widely expressed in murine brain.




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Özge Karayel Eren

Development of sensitive and quantitative proteomics strategies to study phospho- and ubiquitin-signaling in health and disease

RG: Matthias Mann



The Max Planck Society has succeeded in recruiting two renowned scientists. Kikuë Tachibana and John Briggs will now be conducting their research at the MPI of Biochemistry in Martinsried.

The Max Planck Institute of Biochemistry (MPIB) expands its scientific expertise with two new directors: Kikuë Tachibana and John Briggs. Molecular geneticist Kikuë Tachibana has moved with her research group from Vienna to Martinsried. Since August 1, she heads the research department "Totipotency". Together with her team, she studies cells that have the ability to develop into whole organisms. In parallel, structural biologist John Briggs starts his work at the institute. He has moved from Cambridge, UK, to Martinsried and heads the department "Cell and Virus Structure" since September 1. John Briggs and his team will study the structures of viruses as well as fundamental molecular cellular mechanisms.

Martinsried - since August 1 and September 1, respectively, Dr. Kikuë Tachibana and Dr. John Briggs are new full-time directors at MPIB. With the two new researchers, the institute now has nine directors, sharpening the research profile of the Max Planck Society. The new director Tachibana says: “I am delighted to have the opportunity offered by the Max Planck Society to devote our research to uncover the molecular mechanisms underlying the start of life. I am looking forward to collaborate scientifically with my colleagues and to work together for developing the Martinsried campus." John Briggs explains, "Structural biology and method development in microscopy have a long tradition in Martinsried. My team and I, together with our new colleagues in Martinsried, are looking forward to finding out more about how viruses assemble and how they function." 

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