Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Floppy but fast

12.10.2015

Inside cells, communication between the nucleus, which harbours our precious genetic material, and the cytoplasm is mediated by the constant exchange of thousands of signalling 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 at EMBL, Frauke Gräter at the Heidelberg Institute for Theoretical Studies, and Martin Blackledge at Institut de Biologie Structurale, is published in Cell this week.


The ultrafast and yet selective binding allows the receptor (gold) to rapidly travel through the pore filled with disordered proteins (blue) into the nucleus, while any unwanted molecules are kept outside.

Credit: Mercadante /HITS

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 EMBL 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 no hint of rigidity: 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 in Grenoble, France, and Cambridge University, UK.

Media Contact

Sonia Furtado Neves
sonia.furtado@embl.de

 @EMBLorg

http://www.embl.org 

Sonia Furtado Neves | EurekAlert!

More articles from Life Sciences:

nachricht A novel socio-ecological approach helps identifying suitable wolf habitats
17.02.2017 | Universität Zürich

nachricht New, ultra-flexible probes form reliable, scar-free integration with the brain
16.02.2017 | University of Texas at Austin

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Biocompatible 3-D tracking system has potential to improve robot-assisted surgery

17.02.2017 | Medical Engineering

Real-time MRI analysis powered by supercomputers

17.02.2017 | Medical Engineering

Antibiotic effective against drug-resistant bacteria in pediatric skin infections

17.02.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>