News | IMPRS for Molecules of Life

A novel form of cellular logistics

Biophysicists have shown that a phenomenon known as diffusiophoresis, which can lead to a directed particle transport, can occur in biological systems.

In order to perform their biological functions, cells must ensure that their logistical schedules are implemented smoothly, such that the necessary molecular cargoes are delivered to their intended destinations on time. Most of the known transport mechanisms in cells are based on specific interactions between the cargo to be transported and the energy-consuming motor proteins that convey the load to its destination. A group of researchers led by Petra Schwille of the Max Planck Institute for Biochemistry and LMU physicist Erwin Frey, Chair of Statistical and Biological Physics, has now shown for the first time that a form of directed transport of particles can take place in cells, even in the absence of molecular motors. Furthermore, this mechanism can sort the transported particles according to their size, as the team reports in the latest issue of Nature Physics.

Graduation of Alexander Reim

Congratulations on your PhD!

Alexander Reim

Novel proteomic approaches to study gene regulatory interactions

RG: Matthias Mann

Publication of IMPRS-LS student Lukas Henneberg

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Henneberg, L.T., and Schulman, B.A.
Cell Chem Biol, 2021, online ahead of print.
doi: 10.1016/j.chembiol.2021.03.009

Decoding the messaging of the ubiquitin system using chemical and protein probes. Cell chemical biology

Post-translational modification of proteins by ubiquitin is required for nearly all aspects of eukaryotic cell function. The numerous targets of ubiquitylation, and variety of ubiquitin modifications, are often likened to a code, where the ultimate messages are diverse responses to target ubiquitylation. E1, E2, and E3 multiprotein enzymatic assemblies modify specific targets and thus function as messengers. Recent advances in chemical and protein tools have revolutionized our ability to explore the ubiquitin system, through enabling new high-throughput screening methods, matching ubiquitylation enzymes with their cellular targets, revealing intricate allosteric mechanisms regulating ubiquitylating enzymes, facilitating structural revelation of transient assemblies determined by multivalent interactions, and providing new paradigms for inhibiting and redirecting ubiquitylation in vivo as new therapeutics. Here we discuss the development of methods that control, disrupt, and extract the flow of information across the ubiquitin system and have enabled elucidation of the underlying molecular and cellular biology.

Graduation of Julia Bittmann

Congratulations on your PhD!

Julia Bittmann

Cell cycle regulation of structure-selective endonuclease during homologous
recombination

RG: Boris Pfander

Graduation of Kai Libicher

Congratulations on your PhD!

Kai Libicher

Design principles of cell-free replicators

RG: Hannes Mutschler

Publication of IMPRS-LS student Claudia Gonzalez-Leal

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Gonzalez-Leal, C., and Ladurner, A.G.
Mol Cell, 2021, 81, 1367-1369.
doi: 10.1016/j.molcel.2021.03.017

A triskelion of nucleic acids drives protein aggregation in A-T

Mutations in ataxia telangiectasia mutated (ATM) kinase lead to cerebellar neurodegeneration. In this issue of Molecular Cell, Lee et al. (2021) revealed how transcription-induced reactive oxygen species and DNA-RNA hybrids activate PARP enzymes, generating the nucleic acid poly-ADP-ribose, which promotes the accumulation of protein aggregates in A-T-like disorders.

Graduation of Jasmin Weber

Congratulations on your PhD!

Jasmin Weber

Control of Leukocyte Trafficking by the Sympathetic Nervous System

RG: Christoph Scheiermann

Publication of IMPRS-LS student Stefan Bauernfried

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Bauernfried, S., and Hornung, V.
Nat Struct Mol Biol, 2021, 28, 333-336.
doi: 10.1038/s41594-021-00580-y

DPP9 restrains NLRP1 activation

NLRP1 was the first inflammasome-forming sensor to be identified, but only recently has its mode of action been in the spotlight. Two groups now report cryo-EM structures demonstrating how NLRP1 is kept in check by the dipeptidyl peptidase DPP9, and they illuminate how DPP9 inhibition leads to NLRP1 inflammasome activation.

Salt consumption controls autoimmune disease

Researchers at the Max Planck Institute (MPI) of Biochemistry show that increased salt consumption has no negative effect on disease progression but is rather beneficial in a mouse model of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the nervous system. In this autoimmune disease, the myelin sheath of the nerve cells is attacked by the patient's own immune system. Several animal models are available to study the disease. Researchers at the Max Planck Institute of Biochemistry have now been able to show, contrary to the results of other studies, that moderately increased salt consumption in mice has no negative effect on the course of the disease. In transgenic mice that develop spontaneous MS-like disease, increased salt consumption led to a suppression of the disease. This study was published in the journal PNAS.

Sodium chloride, table salt, is an essential mineral that we must consume for a healthy life. However, excessive salt consumption is one of the known health risks, as it has been linked to cardiovascular and kidney diseases. Researchers are also interested in understanding the effect of excessive salt consumption in autoimmune and inflammatory diseases such as MS. Therefore, an animal model of multiple sclerosis called Experimental Autoimmune Encephalomyelitis (EAE) has been used in the past to study the effect of excessive salt consumption. It has been reported that it leads to exacerbation of the disease.

Publication of IMPRS-LS student Michael Bartoschek

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Bartoschek, M.D., Ugur, E., Nguyen, T.A., Rodschinka, G., Wierer, M., Lang, K., and Bultmann, S.
(IMPRS-LS students are in bold)
Nucleic Acids Res, 2021, online ahead of print.
doi: 10.1093/nar/gkab132

Identification of permissive amber suppression sites for efficient non-canonical amino acid incorporation in mammalian cells

The genetic code of mammalian cells can be expanded to allow the incorporation of non-canonical amino acids (ncAAs) by suppressing in-frame amber stop codons (UAG) with an orthogonal pyrrolysyl-tRNA synthetase (PylRS)/tRNAPylCUA (PylT) pair. However, the feasibility of this approach is substantially hampered by unpredictable variations in incorporation efficiencies at different stop codon positions within target proteins. Here, we apply a proteomics-based approach to quantify ncAA incorporation rates at hundreds of endogenous amber stop codons in mammalian cells. With these data, we compute iPASS (Identification of Permissive Amber Sites for Suppression; available at www.bultmannlab.eu/tools/iPASS), a linear regression model to predict relative ncAA incorporation efficiencies depending on the surrounding sequence context. To verify iPASS, we develop a dual-fluorescence reporter for high-throughput flow-cytometry analysis that reproducibly yields context-specific ncAA incorporation efficiencies. We show that nucleotides up- and downstream of UAG synergistically influence ncAA incorporation efficiency independent of cell line and ncAA identity. Additionally, we demonstrate iPASS-guided optimization of ncAA incorporation rates by synonymous exchange of codons flanking the amber stop codon. This combination of in silico analysis followed by validation in living mammalian cells substantially simplifies identification as well as adaptation of sites within a target protein to confer high ncAA incorporation rates.