Cells never forget to take out the trash. It has long been known that cells tag proteins for degradation by labelling them with ubiquitin, a signal described as “the molecular kiss of death”. Tim Clausen’s group at the Research Institute of Molecular Pathology (IMP) in Vienna identified an analogous system in gram-positive bacteria, where the role of a degradation tag is fulfilled by a little known post-translational modification: arginine phosphorylation. The discovery, which is published online by the journal Nature, opens new avenues for designing antibacterial therapies.
Like in the U2 song title Running to stand still, the apparent steady state of cells belies constant production and removal of proteins within. Although research into protein degradation has lagged behind research into protein synthesis, it is now well appreciated that when it comes to proteins, death is just as important as birth – and as tightly regulated. Each is removed at the right moment and special care is taken to eliminate those that are either damaged or perform functions no longer necessary in a particular context.
The degradation process, which consists of chopping the protein substrate into small fragments, takes place inside compartmentalised proteases – specialised molecular machines often likened to paper shredders. If – as in the eukaryotic ubiquitin-based system – the access to the protease depends on a specific tag that must be carried by the substrate, then the important decision who and when should be eliminated boils down to the timely and selective attachment of tags. The mechanism is elegant, yet scientists working with bacteria have been puzzled to find it used by just one specific branch of their organisms of interest. The current study changes the picture.
Tim Clausen’s lab stumbled upon arginine phosphorylation several years ago while studying how certain bacteria cope with adverse conditions. McsB, a protein involved in this process, turned out to have a unique ability to phosphorylate other proteins on arginine residues. While protein regulation by reversible addition of phosphoryl groups had been the mainstay of biochemistry since the Nobel Prize-winning work of Edwin G. Krebs and Edmond H. Fischer in the 1950s, it was now the first time that it had been observed to involve arginine. Follow-up studies have revealed hundreds of modified proteins in the model organism Bacillus subtilis. Although the modification was observed to be regulated in response to environmental conditions, the function has remained elusive.
“There were several reasons why we thought phosphoarginine might be the ‘bacterial ubiquitin’,” says Tim Clausen, for whom protein degradation has long been an area of intense focus. McsB has been known to be transcriptionally co-regulated with a major protease of the bacterium B. subtilis, ClpCP, and was once proposed to function as its “adaptor” that brings in a specific substrate. Tim speculated that it might in fact work more like a “labeler”, tagging many diverse proteins with a “phospho-kiss of death”. In a series of sophisticated experiments, his group proved the hypothesis to be correct.
“I knew we were on the right track when phosphoarginine showed a strong binding affinity to ClpCP,” says Débora Broch Trentini, a postdoc in the Clausen lab and the first author of the Nature paper. It is this interaction, she adds, that accounts for specificity: proteins marked with phosphoarginine are directly captured by the ClpCP protease and shredded to pieces.
As the discovered system is widely conserved across gram-positive bacteria – a large class that includes the notorious human pathogen Staphylococcus aureus – the study explains previous reports that identified McsB and ClpC as virulence factors. To infect, bacteria must overcome stresses encountered within the host and this in turn relies on efficient degradation of stress-damaged proteins. The discovery from Tim’s lab therefore opens a new perspective on how bacteria-mediated disease could be combated.
"We identified the mechanism. The next step is to block it,” concludes Tim Clausen.
For further information, please contact:
+43 1 79730 358
Heidemarie Hurtl | AlphaGalileo
First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife
Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
26.10.2016 | Physics and Astronomy
26.10.2016 | Earth Sciences
25.10.2016 | Earth Sciences