Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Malaria mechanism revealed

29.07.2005


Molecular ’handshake’ of key parasite protein seen as target for drug design and vaccine development



By determining the molecular structure of a protein that enables malaria parasites to invade red blood cells, researchers have uncovered valuable clues for rational antimalarial drug design and vaccine development. The findings are reported in the July 29 issue of the journal Cell.

Malaria causes approximately 400 million clinical cases and 2 million deaths annually, with more than 80% of deaths occurring among children. The disease is caused by mosquito-borne parasites of the genus Plasmodium (primarily Plasmodium falciparum). Following the initial stages of infection, merozoite-stage parasites ("merozoites") invade red blood cells, leading to clinical symptoms and in many cases, death.


"Niraj Tolia [the first author of the study] had malaria when he was young. So when he joined my lab as a graduate student, it didn’t take long for me to convince him that this was a good project," says structural biologist Leemor Joshua-Tor of Cold Spring Harbor Laboratory, who led the research.

A major pathway through which malaria parasites invade red blood cells is the binding of a protein on the surface of merozoites called EBA-175 to a receptor protein on the surface of red blood cells called glycophorin A. Merozoites die if they do not invade red blood cells soon after their release (from liver cells) into the bloodstream. Thus, the binding of EBA-175 to glycophorin A is a prominent target for the development of therapies to control malaria.

To explore the molecular basis of the binding of EBA-175 to glycophorin A--with the rationale that such information might reveal strategies for preventing and treating malaria--the researchers used x-ray crystallography to determine the atomic structure of a key portion of the EBA-175 protein called the RII domain.

The results revealed that two molecules of RII come together in a manner resembling a handshake, and that the overall shape of such RII "dimers" resembles a donut with two holes. (Image available on request)

Next, to identify precisely which parts of the RII surface bind to glycophorin A, the researchers determined the atomic structure of RII crystallized along with sugar molecules called glycans. Previous work by a co-author of the study, Kim Lee Sim of Protein Potential LLC, established that glycans displayed on the glycophorin A receptor are required for RII binding and for the invasion of red blood cells by the malaria parasite.

The new results showed that each RII dimer binds six glycans. Interestingly, these glycans were discovered to be sandwiched between surfaces where the two RII molecules bind to each other when they form their handshake. This finding suggested that the RII handshake interaction serves to clamp the parasite protein onto the glycophorin A receptor of red blood cells. An important idea stemming from this view is that blocking the RII interaction--with drugs or vaccines--should block glycophorin A receptor binding and forestall malaria infection.

To test this idea, the researchers created altered versions of the RII protein that they predicted would block the RII handshake, glycan binding, or both. The result: All such altered versions of the RII protein failed to bind to red blood cells, confirming the idea that drugs or vaccines that block the RII interaction, glycan binding, or both might be effective therapies for malaria. (Image available on request)

"We now see precisely how a key part of a malaria parasite protein works. This enables researchers to design very specific wrenches to throw into the works. The EBA-175 protein and others related to it appear to be unique to Plasmodium, so they are excellent drug and vaccine targets," says Joshua-Tor.

Joshua-Tor, Tolia, and Sim were joined in the study by Eric Enemark of Cold Spring Harbor Laboratory.

Peter Sherwood | EurekAlert!
Further information:
http://www.cshl.edu

More articles from Life Sciences:

nachricht Fingerprint' technique spots frog populations at risk from pollution
27.03.2017 | Lancaster University

nachricht Parallel computation provides deeper insight into brain function
27.03.2017 | Okinawa Institute of Science and Technology (OIST) Graduate 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: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Northern oceans pumped CO2 into the atmosphere

27.03.2017 | Earth Sciences

Fingerprint' technique spots frog populations at risk from pollution

27.03.2017 | Life Sciences

Big data approach to predict protein structure

27.03.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>