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Looking at the control of cellular homeostasis

Many biological processes that occur in our body are driven and controlled by protein complexes. In order to better understand these processes, biochemist Prof. Dr. Florian Stengel from the University of Konstanz is developing methods that will eventually make it possible to study the architecture, interactions and general dynamics of intact protein complexes quantitatively and in detail. Stengel combines structural mass spectrometry methods with computer-assisted modelling.

Schematic representation of the methods: i) Structural data are generated by multiple methods, predominantly mass spectrometry, and are used alongside available data from databases. ii) The system is represented as a collection of rigid bodies and beads on a flexible string. iii) An ensemble of structures that are consistent with the experimental data is obtained by conformational sampling. iv) The ensemble is analysed and validated. © Erzberger, Stengel, Pellarin et al., Cell, 2014

Although the study of protein complexes and their relevance in the body has made huge progress in recent years, we still have a rather inaccurate idea of how these proteins interact with each other on the level of intact macromolecular protein assemblies. Florian Stengel, a biochemist and junior professor at the University of Konstanz, has been head of the Laboratory of Cellular Proteostasis and Mass Spectrometry since 2015. His team is specifically focused on research into the structure and dynamics of intact large protein assemblies as well as the development and application of hybrid approaches that combine multiple strategies for analysing such complex structures. “Little is yet known about the dynamic nature of the interaction of intact protein complexes on the molecular level. We are therefore trying to understand how this interaction works. We particularly want to understand how the protein content of a cell is regulated as this is essential for cellular homeostasis,” says Stengel. Homeostasis refers to internal processes that maintain the stability of the body’s internal environment in response to external changes.

Glossary

  • The proteome is the entirety of all proteins expressed by a cell, tissue or organism at a particular time and under specific conditions.
  • Biochemistry is the study of the chemical processes in living organisms. Therefore it touches the studies of chemistry and biology as well as physiology.
  • Biomolecules which can bind active agents are called targets. They can be receptors, enzymes or ion channels. If agent and target interact with each other the term agent-target-specific effect is used. The identification of targets is very important in biomedical and pharmaceutical research because a specific interaction can help to understand basic biomolecular processes. This is essential to identify new points of application.

New research group advances insights into the structure of protein complexes

Biochemist Prof. Dr. Florian Stengel is developing methods that facilitate the analysis of the dynamic balance of cellular proteins. © Prof. Florian Stengel / Universität Konstanz

Stengel has been awarded around 1.2 million euros under the German Research Foundation’s (DFG) Emmy Noether programme to establish a junior research group and drive his research forward. Funding will be provided for a period of five years during which he and his team aim to develop methods that they can use to obtain detailed insights into the dynamic homeostasis of cellular proteins. “We are still a very small research group, consisting of myself, a scientific assistant and two doctoral students. However, we hope to grow and are looking for qualified doctoral students and post-docs,” says Stengel.

The researchers hope that their research project will contribute to increasing understanding of the structure of protein complexes. The aim is to analyse a number of components that are crucial for proteostasis on the level of large intact protein assemblies. “We hope that this will help us close a gap between conventional high-resolution structural biology approaches and system-wide proteomics approaches,” explains the biochemist. Structural biology methods such as X-ray crystallography can be used to analyse individual protein complexes while system-wide proteomics approaches primarily target the individual protein or peptide level, even though they enable the large-scale study of protein structure and functions.

Combining the methods to achieve success

“I am therefore particularly focused on a hybrid approach in the hope that this will help us elucidate the structural cohesion of any macromolecular protein or protein complex assembly, and thus broaden our knowledge of these key cellular modules,” says Stengel who investigates cellular proteostasis using conventional biochemistry methods combined with new proteomics approaches. In addition to mass spectrometry methods and computer-assisted modelling, the team will also use state-of-the-art sequencing methods.

“The research project has just begun. But we hope that in five years’ time, our work will contribute to a better understanding of the function of some of these complex homeostatic mechanisms in the cell,” concludes Stengel. The results will initially be important mainly for basic research, but some of the methods might eventually be used in applied research or for diagnostic purposes.

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