Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

How cells take out the trash: the “phospho-kiss of death” deciphered

07.10.2016

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.


Phosphoarginine functions as a protein degradation tag in Gram-positive bacteria analogous to ubiquitin in eukaryotes

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.

http://www.nature.com/nature/journal/vaap/ncurrent/full/nature20122.html

  • Full bibliographic informationTrentini, DB, et al. (2016) “Arginine phosphorylation marks proteins for degradation by a Clp protease”. Nature Accelerated Article Preview, October 6, 2016.

For further information, please contact:

Heidemarie Hurtl

+43 1 79730 358

hurtl@imp.univie.ac.at

Heidemarie Hurtl | AlphaGalileo

More articles from Life Sciences:

nachricht Repairing damaged hearts with self-healing heart cells
22.08.2017 | National University Health System

nachricht Biochemical 'fingerprints' reveal diabetes progression
22.08.2017 | Umea University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Cholesterol-lowering drugs may fight infectious disease

22.08.2017 | Health and Medicine

Meter-sized single-crystal graphene growth becomes possible

22.08.2017 | Materials Sciences

Repairing damaged hearts with self-healing heart cells

22.08.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>