Navigation Links
Malaria mechanism revealed

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 av ailable 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.


'"/>

Source:Cold Spring Harbor Laboratory


Related biology news :

1. Malaria killing a million a year
2. Malaria parasites develop in lymph nodes
3. Malaria, potato famine pathogen share surprising trait
4. Malaria vaccine prompts victims immune system to eliminate parasite from mosquitoes
5. Twenty Years of Malaria Research: Outcomes and Perspectives
6. Malaria treatment efficacy compromised in certain HIV-positive patients
7. Malaria may fuel spread of HIV in sub-Saharan Africa
8. A new mechanism of regulating RNA degradation
9. Plants, animals share molecular growth mechanisms
10. PET/MRI scans may help unravel mechanisms of prenatal drug damage
11. Researchers discover molecular mechanism that desensitizes us to cold
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:5/20/2016)... 20, 2016  VoiceIt is excited to announce ... By working together, VoiceIt and VoicePass ... and VoicePass take slightly different approaches to voice ... security and usability. ... new partnership. "This marketing and technology ...
(Date:5/12/2016)... , May 12, 2016 WearablesResearch.com ... just published the overview results from the Q1 wave ... the recent wave was consumers, receptivity to a program ... data with a health insurance company. "We ... to share," says Michael LaColla , CEO of ...
(Date:5/3/2016)... VILNIUS, Lithuania , May 3, 2016 /PRNewswire/ ... today released the MegaMatcher Automated Biometric Identification ... deployment of large-scale multi-biometric projects. MegaMatcher ABIS can ... and accuracy using any combination of fingerprint, face ... of MegaMatcher SDK and MegaMatcher ...
Breaking Biology News(10 mins):
(Date:6/24/2016)... ... , ... While the majority of commercial spectrophotometers and fluorometers use the z-dimension ... are higher end machines that use the more unconventional z-dimension of 20mm. Z-dimension ... bottom of the cuvette holder. , FireflySci has developed several Agilent flow cell ...
(Date:6/23/2016)... , June 23, 2016   Boston Biomedical ... novel compounds designed to target cancer stemness pathways, ... been granted Orphan Drug Designation from the U.S. ... of gastric cancer, including gastroesophageal junction (GEJ) cancer. ... designed to inhibit cancer stemness pathways by targeting ...
(Date:6/23/2016)... (PRWEB) , ... June 23, 2016 , ... ... Plate® YM (Yeast and Mold) microbial test has received AOAC Research Institute approval ... of microbial tests introduced last year,” stated Bob Salter, Vice President of Regulatory ...
(Date:6/23/2016)... ... June 23, 2016 , ... ... the launch of the Supplyframe Design Lab . Located in Pasadena, Calif., ... the future of how hardware projects are designed, built and brought to market. ...
Breaking Biology Technology: