A research team at Columbia University announced on June 30 that they have captured the first high-resolution images of the moving junction, a structure used by malaria parasites to invade human red blood cells. The study, published in Cell, overturns decades-old assumptions about how the parasite enters cells and suggests new avenues for antimalarial drug development.
For nearly fifty years, scientists have known that malaria parasites enter red blood cells through a ring-shaped structure called the moving junction. However, its exact function remained unclear due to its brief existence—assembling and dissipating within 60 seconds during invasion. The Columbia researchers froze parasites at the onset of invasion and extracted the intact complex from cells. Using cryo-electron microscopy, they obtained detailed three-dimensional images of the AMA1-RON protein complex that forms the core of the moving junction.
The structural data revealed that rather than acting as a passive doorway, “the moving junction turns out to be a molecular machine that actively remodels the host cell's membrane to help the parasite force its way inside,” Meseret Haile, first author and PhD candidate in Ho's lab, 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.”
To further investigate this mechanism, researchers synthesized components of these wedge-like helices from parasites and tested their effects on artificial membranes. The results showed that intact helices could thin and puncture membranes while weakened versions did not affect them. Building on their findings, they used machine learning-powered protein design tools along with structural information to create mini-proteins aimed at blocking this interaction. Their best candidate blocked parasites from invading red blood cells without harming already-infected ones.
While this designed mini-protein is only an initial proof-of-concept—not yet suitable for clinical use—the study demonstrates new strategies for targeting malaria infection at its source by interfering with entry into red blood cells. Daphne Kaxiras, MD-PhD student who led inhibitor design work, 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.”
The approach may also apply broadly across other difficult-to-study pathogens by capturing fragile complexes directly from organisms and using them as guides for therapeutic design.
