For nearly fifty years, scientists have known that malaria parasites slip into human red blood cells through a fleeting ring-shaped structure called the moving junction. The structure appears, does its job, and vanishes in under a minute, too fast for anyone to see what it really does.
But now, researchers at Columbia University froze the parasite during its invasion and extracted its intact complex directly from inside the cell. What they discovered challenged decades of belief: the moving junction is not a passive door; it is an active molecular machine that changes the host cell membrane and enables protist-mediated internalization.
The moving junction was first glimpsed in 1978 as a mysterious thickening of the membrane where the parasite meets the cell. Researchers eventually found the four key proteins, aka AMA1, RON2, RON4, and RON5, that make it up, but its function was still unknown.
Chi-Min Ho, senior author of the new study, explained: “We’ve known for decades that this structure is essential for the parasite to get into a cell, but not how it actually works. Pulling it directly out of the parasite intact lets us finally ask that question directly.”
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The team also used a compound that inhibited the parasite’s motor without completely blocking junction formation to freeze parasites half in red blood cells. Next, they used cryo-electron microscopy to capture the three-dimensional structure of the AMA1-RON complex in atomic detail.
The structure resembled a sailboat: AMA1 forming a “sail” above the cell surface, while the RON proteins created a broad “hull” pressed against the membrane.
The hull revealed the secret. Its surface was covered with positively charged anchors and wedge-like helices,
Classic features of cellular machines that bend and reshape membranes.
Meseret Haile, the study’s first author, said: “It had been pictured as a kind of series of staples or spot-welds, making up a passive ring the parasite hauls itself through. What we see instead is a machine built to reshape the host cell’s own membrane. That changes how we think about the whole event.”
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Tests confirmed the wedges could deform artificial membranes, thinning and puncturing them. The moving junction, it seems, works hand-in-hand with the parasite’s motor to lever the parasite inside.
The discovery goes beyond solving a decades-old puzzle. The team used the structure as a blueprint to design a mini-protein inhibitor that blocks invasion. Their best candidate prevented parasites from entering red blood cells in a dose-dependent way, without harming already-infected cells.
Daphne Kaxiras, who led the inhibitor design, said: “Once we could see the target in its real setting, designing something to block it became a tractable problem. That’s the part we’re most eager to build on.”
Although this mini-protein is just a proof of concept, it illustrates an alternative strategy: developing invasion-interdicting molecules directly from structures that are nearly native to the parasite. The same insights also illuminate how existing antibodies operate, which may contribute to vaccine design.
Malaria still kills around 600,000 people each year, mostly children in sub-Saharan Africa. It’s this ability of the parasite to invade red blood cells that perpetuates a lethal cycle of fevers and reinfections. This is particularly important because the moving junction is used across parasite species and life stages, meaning that blocking it could prevent infection without enabling widespread resistance.
By finally catching the moving junction in the act, Columbia’s team has opened a new front in the fight against malaria, transforming a long-standing mystery into a roadmap for future drugs and vaccines.
Journal Reference:
- Meseret Haile, Daphne Kaxiras et al. Structural basis for host membrane binding and remodeling by invading malaria parasites. Cell. DOI: 10.1016/j.cell.2026.06.012
