Inside cells, communication between the nucleus and the cytoplasm is mediated by the constant exchange of thousands of signaling molecules and proteins. Until now, it was unknown how this protein traffic can be so fast and yet precise enough to prevent the passage of unwanted molecules. Through a combination of computer simulations and various experimental techniques, researchers from Germany, France and the UK have solved this puzzle: A very flexible and disordered protein can bind to its receptor within billionths of a second. Their research, led by Edward Lemke (EMBL), Frauke Gräter (HITS), and Martin Blackledge (IBS) is published in “Cell” this week.
Proteins can recognize one another. Each engages very specifically with only a subset of the many different proteins present in the living cell, like a key slotting into a lock. But what if the key is completely flexible, as is the case for so-called intrinsically disordered proteins (IDPs)?
The research teams headed by Edward Lemke at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Frauke Gräter at the Heidelberg Institute for Theoretical Studies (HITS) and Martin Blackledge at the Institut de Biologie Structurale, (IBS) in France, addressed this question in a highly interdisciplinary collaboration, combining molecular simulations, single molecule fluorescence resonance energy transfer (FRET), nuclear magnetic resonance (NMR), stopped flow spectroscopy and in-cell particle tracking.
Unexpectedly, they found that flexible, spaghetti-like proteins can be good – maybe even better than solid protein blocks – at being recognised by multiple partners. And they can do so very fast, while still retaining the high specificity the cell needs. In fact, this could be why these disordered molecules are more common in evolutionarily higher organisms, the researchers surmise.
Researchers had assumed that when an IDP ‘key’ needed to bind to its lock, it rearranged itself to become more rigid, but experiments in the Lemke lab hinted otherwise. “The pioneering single molecule experiments undertaken at EMBL showed for the particular interaction of a receptor with a disordered protein just nothing: the flexible protein stayed as flexible even when bound to its receptor” says Davide Mercadante (HITS).
This prompted him to study the very same interaction on the computer. The surprising result was that the high flexibility of the IDP actually helps it bind to its lock – in this case, a nuclear transport receptor, which shuttles proteins into the nucleus. The simulations even suggested the binding to be ultrafast – faster than any other association of that kind recorded to date.
"The computational data indicated that we might have identified a new ultrafast binding mechanism, but it took us three years to design experiments to prove the kinetics in the lab,” Iker Valle Aramburu (EMBL) recalls. “In the end, we had a remarkably perfect match."
The results now help to understand a long-standing paradox: “For a cell to be viable, molecules must constantly move into and out of its nucleus”, says Edward Lemke (EMBL). ”Our findings explain the so-called transport paradox – that is, how this shuttling can be so very fast while remaining specific so that unwanted molecules cannot pass the barrier that protects our genome.”
The new study suggests that many binding motifs at the surface of the IDP create a highly reactive surface that together with the very high speed of locking and unlocking ensures efficient proof-reading while the receptors to travel so fast through a pore filled with other IDPs.
“This is likely a new paradigm for the recognition of intrinsically disordered proteins.” says Frauke Gräter (HITS). Since around 30-50% of the proteins in human cells are disordered, at least in some regions of the protein, the results may also provide a rationale for how recognition information can be processed very fast in general - which is vital to cells.
Other researchers involved in the study are working at the IBS Grenoble / France, and Cambridge University / UK.
Publication in “Cell”, Plasticity of an ultrafast interaction between nucleoporins and nuclear transport receptors
Sigrid Milles, Davide Mercadante, Iker Valle Aramburu, Malene Ringkjøbing Jensen, Niccolò Banterle, Christine Koehler, Swati Tyagi, Jane Clarke, Sarah L Shammas, Martin Blackledge, Frauke Gräter, Edward A Lemke
Sonia Furtado Neves
EMBL Press Officer & Deputy Head of Communications
Tel.: +49 (0)6221 387 8263
Fax: +49 (0)6221 387 8525
Dr. Peter Saueressig
Head of Communications
Heidelberg Institute for Theoretical Studies (HITS)
Dr. Frauke Gräter
Heidelberg Institute for Theoretical Studies (HITS)
Dr. Edward Lemke
Structural and Computational Biology Unit, Cell Biology and Biophysics Unit, (EMBL)
Phone: +49-6221-387 8536
http://www.h-its.org/en-presse/in-cell-floppy-but-fast/ HITS press release
http://www.cell.com/cell/abstract/S0092-8674%2815%2901264-7 Publication in "Cell"
Dr. Peter Saueressig | idw - Informationsdienst Wissenschaft
What the world's tiniest 'monster truck' reveals
23.08.2017 | American Chemical Society
Treating arthritis with algae
23.08.2017 | Empa - Eidgenössische Materialprüfungs- und Forschungsanstalt
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,...
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...
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...
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...
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...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
23.08.2017 | Life Sciences
23.08.2017 | Life Sciences
23.08.2017 | Physics and Astronomy