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 Single-stranded DNA and RNA origami go live
15.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard

nachricht New antbird species discovered in Peru by LSU ornithologists
15.12.2017 | Louisiana State 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: First-of-its-kind chemical oscillator offers new level of molecular control

DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.

Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Engineers program tiny robots to move, think like insects

15.12.2017 | Power and Electrical Engineering

One in 5 materials chemistry papers may be wrong, study suggests

15.12.2017 | Materials Sciences

New antbird species discovered in Peru by LSU ornithologists

15.12.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>