Unleashing the shredder: Understanding cellular maintenance

Dr Björn M Burmann, from the University of Gothenburg, outlines the cellular clean-up process from a molecular level.

In the real world, waste is normally disposed of and a similar process also needs to be achieved within the biological context of the cell to get rid of broken and possible harmful proteins. Where this task would be achieved in the outside world by a cleaning team, this job is carried out in cells by proteins known as proteases. These proteases work in close relationship to another class of proteins, molecular chaperones, that might be able to rescue and salvage some misfolded proteins to regain their functionality. These processes are of great importance for the cellular fitness, as you can imagine what happens when a maintenance crew is on strike in a big city. A non-functional system in the cells can also directly lead to a non-functional cell through the accumulation of broken proteins, a problem found at the onset of a wide range of severe diseases.

Maintaining cellular fitness

Researchers from the Department of Chemistry and Molecular Biology and the Wallenberg Centre for Molecular and Translational Medicine of the University of Gothenburg, Sweden, used Escherichia coli  – a bacterium found in the human gut microbiota that has adapted to survive under a wide variety of different environmental stress conditions – as a model system. Within this bacterial species, one of the main components of the bacterial stress response to heat is an enzyme called DegP – a protease which can shred unstable proteins to prevent them from accumulating in the cell envelope of bacteria. DegP is inactive at low temperatures and only becomes active at elevated temperatures, however, the molecular mechanism underlying its activation remained unknown so far.

Fig. 1. Methionine – methyl region of a 2D [13C, 1H]-NMR spectrum of a PDZ1-PDZ2 domain construct of DegP measured at 25°C to 50°C as indicated. Spectra were manually shifted along the 1H dimension to illustrate the transition between open and locked states (top left). Analysis of the open and locked state. Lines are a guide to the eyes only (bottom left). Observed NMR effects indicative for an interaction between both parts of the protein reveal a hydrophobic patch, stabilising the PDZ1-PDZ2 interaction. Residues involved on the PDZ2 side are highlighted in green, whereas residues on the PDZ1 side are highlighted in purple. Adapted from Sulskis et al.1.
Using advanced nuclear magnetic resonance (NMR) techniques, the team led by Associate Professor Björn M Burmann was able to show in a recent study in Science Advances1 how DegP is activated via a molecular temperature switch.

Dr Burmann explained: “DegP in the inactive resting state forms a stable hexamer – a protein formed by six subunits – which splits into trimers (of three subunits) as the temperature increases. This splitting unleashes the destructive activity of the protease, allowing it to efficiently remove unwanted proteins. By using nuclear magnetic resonance (NMR) spectroscopy, the team could show in detail how this mechanism is governed by two regulatory domains of DegP. At low temperatures, these domains are stabilised by a molecular lock forming the hexamer. However, at high temperatures, the individual domains become more dynamic and consequently separate into active trimers (Fig. 1).

Cellular Structure
Fig. 2: Previously determined crystal structure of DegP 24-mer, forming a highly effective proteolytic cage is stabilised by a specific interaction between two substrate-recognising PDZ domains. Based on the X-Ray structure determined by Krojer et al.2.

“Remarkably, DegP exploits a similar interdomain lock to stabilise the proteolytic cage for efficiently shred misfolded proteins that could be structurally described already before by X-ray crystallography (Fig. 2).

“Overall, the newly characterised built-in activation mechanism permits DegP self-regulation (Fig. 3), which can be hopefully exploited for antimicrobial drug research. Furthermore, this molecular activation mechanism seems to be evolutionarily conserved for this class of proteins, providing also fresh new insight for related human proteases involved in different types of cancer and neurodegeneration.”


Proteases are enzymes, biological catalysts, that facilitate proteolysis – the break-down of proteins into smaller peptides or even individual amino acids.

The research was carried out using the outstanding NMR spectroscopy infrastructure at the Swedish NMR Centre, hosted by the University of Gothenburg.

Fig. 3: In cellular ground states at low temperature, the PDZ1-PDZ2 interaction results in an inactive DegP hexamer. Under heat-shock conditions, this interaction is broken, leading to trimerisation of DegP. At low temperatures, the protease activity of DegP can be triggered by activating substrates, which mediate the formation of proteolytic (12/24-mer) cages via a transient trimerisation through interactions with the PDZ1 domain. Upon temperature activation, the interdomain lock mediates the transformation of DegP from the locked inactive hexameric stateto an open trimeric state, primed for the proteolytic degradation of substrates. Adapted from Sulskis et al.1.

This research was made possible by generous funding by the Knut och Alice Wallenberg Foundation (BMB), the Vetenkapsrådet (BMB,) as well as an EMBO Long-Term Fellowship to co-author Johannes Thoma.


1          Šulskis, D., Thoma, J. & Burmann, B. M. Structural basis of DegP protease temperature-dependent activation. Sci. Adv. 7 (2021).

2          Krojer, T. et al. Structural basis for the regulated protease and chaperone function of DegP. Nature 453, 885-890 (2008).

Please note, this article will also appear in the ninth edition of our quarterly publication.

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Dr Björn M. Burmann

Burmann Group, Department of Chemistry and Molecular Biology, University of Gothenburg
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