Current Research Questions

Spatial-numerical regulation of transmembrane protein assemblies

The correct spatio-numerical regulation of transmembrane protein assemblies is of outermost importance for all living organisms. How transmembrane protein assemblies are correctly localized and how their number is exactly restricted is only poorly understood.  

 

Flagella are the engines of bacterial motility and represent one of the largest transmembrane protein assemblies in the biosphere. They appear in defined numbers and localization at the surface of a given microbial species (flagellation pattern). Because the phenotypic appearance of flagellation patterns can be easily addressed by microscopy, it offers an excellent ‘phenotype’ for investigating the molecular mechanisms and inventory that control bacterial self-organization. Major questions are: Which molecular mechanisms dictate place and number of bacterial flagella? Which mechanisms dictate diversity of flagellation patterns and how did they evolve during the course of molecular evolution? To which extent are mechanisms of ‘localized’ transcription and translation are critical for establishing place and number of flagella? 

 

 

Interested? Here are some more Info: 

 

Schuhmacher J, Thormann KM and Bange G (2015). How bacteria maintain location and number of flagella. FEMS Reviews Microbiology, 39(6):812-22

Metabolic- and Stress-signaling Networks

The ability of living organisms to adapt their metabolism to nutrient limitation or environmental changes is of outermost importance for survival. Central to this process are the nutritional alarmones pppGpp and ppGpp (collectively named: (p)ppGpp) that globally reprograms replication, transcription, translation and metabolism. In general, the cellular alarmone pool is regulated by (p)ppGpp synthesizing, converting and degrading enzymes. Activity of these enzymes is modulated by a variety of intracellular and extracellular signals allowing their direct translation into alarmone levels.

Interestingly, different bacterial species and the plant chloroplasts employ diverging sets of enzymes to maintain their (p)ppGpp metabolism. We would like to understand why this is the case from a molecular and systems biology perspective.

 

Interested? Here is some more Info: 

 

Steinchen W & Bange G (2016). The magic dance of the alarmones (p)ppGpp. Molecular Microbiology101(4):531-44

Protein Homeostasis & Translation control

Protein homeostasis is crucial for all living cells because protein abundance directly correlates with activity. Major mechanisms of controlling protein abundance involve regulation of transcription, translation and protein degradation. While these three processes including their mechanisms and constituents involved are well understood; many possibilities might exist to modulate their modus operandi with respect to environmental adaptation.

For example, by investigating the synthesis of flagellin, a highly abundant building block of the flagellum with over 20.000 copies, we could show that regulation of translation initiation by the CsrA protein is handled by mechanisms that fundamentally differ between bacterial species. While the g-proteobacteria employ small RNAs (sRNAs) to regulate CsrA, the Firmicutes as well the e-proteobacteria use the ancient FliW protein instead (Altegoer et al., Bange, PNAS, 2016). The reason for this adaptation remains to be clarified, but nicely illustrates that protein homeostasis is subject to molecular plasticity during microbial adaptation.

On the other hand, stability and turnover of highly abundant proteins such as Flagellin varies between the species by the presence of specific adaptor proteins targeting their clients to the proteasome for degradation (Altegoer & Bange; unpublished). Why different microorganisms have invented different solutions for the same problem will be an important research theme.

Interested? Here is some more info: 

 

Altegoer FA, Rensing S, Bange G (2016).Structural basis for the CsrA-dependent modulation of translation initiation by an ancient regulatory protein.

PNAS113(36):10168-73

Altegoer F, Bange G (2015). Undiscovered regions on the molecular landscape of flagellar assembly.

Current Opinion in Microbiology, 28:98-105

 

Structural evolution of CRISPR-Cas dependent immunity

CRISPR-Cas systems are adaptive immune systems against invading nucleic acids. Sequence information of previously encountered invading nucleic acids is typically stored in CRISPR arrays, which allow for a target specific programming of CRISPR-Cas surveillance and effector complexes to counter recurrent invasion. Interestingly, although the CRISPR-Cas machinery that extends the CRISPR array upon novel threads is highly conserved, the surveillance and effector modules diversified substantially. 

 

The ongoing ‘bacteria-virus’ arms race is supposed to be the main driving force of the continuing co-evolution and structural diversification of bacterial defense and viral CRISPR evasion mechanism. Furthermore, non-canonical functions such as transcriptional control, stress response and pathogenicity development might have contributed to the evolution of additional CRISPR-Cas features. We are interested in the structural and mechanistic aspects underlying this diversification. 

 

Central objectives are: How are primary functions maintained with different components? How do varied components alter mechanisms? How are additional functions enabled?

Read more:

Pausch P, Müller-Esparza H, Gleditzsch D, Altegoer F, Randau L, Bange G (2017). Structural variation of type I-F CRISPR RNA guided DNA surveillance.

Molecular Cell, DOI: http://dx.doi.org/10.1016/j.molcel.2017.06.036

Non-Ribosomal Peptide Synthetases (NRPS)

NRPSs are multimodular enzymes enabling the production of highly modified peptides from enormous spectrum of proteinogenic and non-proteinogenic amino acids. By contrast to the ribosome, NRPSs act independent of messenger RNA (mRNA). Therefore, the information for the respective peptide synthesized by an NRPS is encoded within its modular architecture. Therefore, each NRPS can only synthesize one peptide (sometimes with minor deviations).

While the molecular structure of individual NRPS modules is roughly understood, a three dimensional understanding of multimodular architecture is still lacking. We therefore aim at a structural understanding of multimodular NRPs enzymes at high resolution by means of X-ray crystallography and cryo-electron microscopy (cryo-EM).

This structural information is of particular interest to gain insights into the underlying architectonical principles, which might be required for the rational design of synthetic NRPSs with novel catalytic features.

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