Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Structural genomics accelerates protein structure determination

28.10.2010
New strategy sheds light on membrane protein structure

Membrane proteins are of immense biological and pharmaceutical importance. But so far there are only a handful of cases in which the exact structure could be successfully determined.


View into the SLAC1 anion channel

Scientists at Columbia University, New York, and Technische Universitaet Muenchen (TUM) have now succeeded in working out the structure of an important ion channel via the analysis of related proteins. The current issue of the journal Nature reports on their findings.

Proteins are molecular machines that transport substances, catalyze chemical reactions, pump ions, and identify signaling substances. They are chains of amino acids and the individual amino acid sequence is known for many of them. However, the functions a protein can carry out inside the cell are determined by the three-dimensional spatial structure of the protein. Establishing this so-called tertiary structure presents a great challenge to scientists.

There is, thus, a lot of catching up to be done in structure analysis. To push progress, the National Institute of General Medical Sciences (NIGMS) of the USA National Institutes of Health (NIH) has invested over 500 million dollars in this field over the last ten years as part of the Protein Structure Initiative with the hope of making significant progress in medicine and biological research.

Informatics professor Burkhard Rost and Marco Punta, Carl von Linde Junior Fellow at the Institute for Advanced Study (IAS) of the TU München, are involved in this large-scale project. They are affiliated with the New York Consortium on Membrane Protein Structure (NYCOMPS), which is among nine funded membrane research centers. The NYCOMPS scientists put a special emphasis on membrane proteins. That is because they play a key role in pharmacological research. When a pharmaceutical agent enters the cell, it normally interacts first with membrane proteins. Knowing the protein structure is essential to understanding this interaction at the molecular level.

However, in the case of these very important membrane proteins, experimentally deciphering the tertiary structure is particularly difficult. For example the recombinant production of many membrane proteins is a major challenge and purification and crystallization are also difficult steps. The result: although around 25 percent of all proteins are membrane proteins, they account for less than one percent of the total number of proteins with known structures. Membrane protein structures are thus underrepresented 25-fold. Given their medical relevance, they should be much better known.

Since the experimental analysis of a membrane protein can take up to several years, the NYCOMPS scientists applied a bioinformatics strategy, the so-called homology modeling. The basic assumption of this strategy is that proteins with common evolutionary predecessors resemble each other in their amino acid sequences, as well as in their three-dimensional structure. If the structure of one of the related proteins can be determined experimentally, the remaining ones can be predicted.

In the case of the bacterial membrane protein TehA they could bring all pieces of the puzzle together. “In a screening procedure we searched for TeHA-related membrane proteins by comparing tens of thousands of amino acid sequences. Using a multistage selection process we chose 43 proteins from 38 different organisms,” says TUM computational biologist Marco Punta.

Scientists at Columbia University now succeeded in experimentally determining the tertiary structure of the membrane protein TehA of the bacterium Haemophilus influenzae using X-ray crystallography. With a resolution of 0.12 nanometers (1.2 Ångstrøm), this structure is among the best crystal structures ever obtained for a membrane protein. Furthermore, the experiment harbored a surprise: The TehA membrane protein has a hitherto entirely unknown fold.

After getting to know the “TehA family,” the scientists at Columbia University succeeded in deriving the structures of the individual proteins. In particular, they modeled the structure of the plant membrane protein SLAC1. Comparing this to the protein structure of TehA derived experimentally, they could build a structural model for SLAC1 – entirely without experimentation, using nothing but bioinformatics methods.

“Using this procedure we aim to have a high structure determination throughput rate. determining more protein structures in a shorter time – that was our goal, in particular for the membrane proteins. The results at hand show that this strategy can work for membrane proteins, too,” says Burkhard Rost.

Ultimately, the three-dimensional structures are determined to identify the function of the proteins using mutagenesis tests. Although the membrane proteins TehA and SLAC1 are only distantly related – the overlap of the amino acid sequence is only 19 percent – the predicted tertiary structure of SLAC1 was so good that a new hypothesis on the function of the SLAC1 membrane protein could be put forward.

SLAC1 is found in the stomata of the plant Arabidopsis thaliana. Stomata control the exchange of water vapor and carbon dioxide between the plant and its environment. This is very important in photosynthesis. The membrane protein SLAC1 plays a role in this process, as well, as part of the anion channel: It influences the turgor pressure – the pressure of cell fluid on the cell wall – and thus the gas exchange of the plant cell as a reaction to environmental influences such as aridity and high carbon dioxide concentration.

SLAC1 anion channels are entirely novel in structure and, apparently, in the mechanism for ion conductance. The SLAC1 pore has a relatively uniform diameter, but in the middle a Phenylalanine-group blocks the way. The results suggest that this amino acid is turned away when the ion channel is activated through binding of a triggering protein.

Publication:

Chen Y.-H. et al. Homologue structure of the SLAC1 anion channel for closing stomata in leaves Nature 467: 1074-1080, 2010 – DOI: 10.1038/nature09487

Contact:

Prof. Dr. Burkhard Rost
Technische Universitaet Muenchen
Institute for Informatics
Boltzmannstr. 3, 85748 Garching, Germany
Tel.: +49 89 289 17808
Kontakt: presse@tum.de

Dr. Andreas Battenberg | EurekAlert!
Further information:
http://www.nycomps.org
http://www.tum.de

More articles from Life Sciences:

nachricht The birth of a new protein
20.10.2017 | University of Arizona

nachricht Building New Moss Factories
20.10.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Terahertz spectroscopy goes nano

20.10.2017 | Information Technology

Strange but true: Turning a material upside down can sometimes make it softer

20.10.2017 | Materials Sciences

NRL clarifies valley polarization for electronic and optoelectronic technologies

20.10.2017 | Interdisciplinary Research

VideoLinks
B2B-VideoLinks
More VideoLinks >>>