A team at Columbia University obtained the first high-resolution three-dimensional structure of the malaria parasite's moving junction and designed a mini-protein to block its function, publishing their findings in the journal Cell on June 30, 2026. The moving junction is a molecular machine that actively remodels the host cell's membrane to assist parasite entry.

Scientists have known for nearly half a century that malaria parasites enter human red blood cells through the moving junction, which assembles, functions, and dissipates within 60 seconds. In 1978, scientists first observed a thickening of the membrane where the parasite meets the cell in electron microscopy images. The researchers froze parasites at the onset of invasion and extracted the intact complex from the cell.

The team used a compound to halt the parasite's internal motor without preventing the junction from forming. They then extracted the fully assembled AMA1-RON complex and imaged it using cryo-electron microscopy. Chi-Min Ho, Assistant Professor in the Department of Microbiology and Immunology at Columbia University Vagelos College of Physicians and Surgeons, stated, "We've known for decades that this structure is essential for the parasite to get into a cell, but not how it actually works." Ho, the study's senior author, added, "Pulling it directly out of the parasite intact let us finally ask that question directly."

Researchers identified four parasite proteins—AMA1, RON2, RON4, and RON5—that assemble into the moving junction's basic building block. All four proteins are essential for malaria parasite invasion, and the machinery is used across every species and stage of the parasite's life cycle. The AMA1 protein forms a 'sail' above the cell surface, while RON2, RON4, and RON5 form a 'hull' pressed against the membrane. The face of the moving junction pressed against the host membrane is covered with positively charged anchors and studded with short helices that penetrate the membrane.

The researchers synthesized the parasite's wedge-like helices and added them to artificial membrane bubbles, which caused the membranes to thin and puncture. Weakened versions of these helices left the artificial membrane bubbles intact. Meseret Haile, the study's first author and a PhD candidate, noted, "It had been pictured as a kind of series of staples or spot-welds, making up a passive ring the parasite hauls itself through." Haile said, "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."

The team, including MD-PhD student Daphne Kaxiras who led the inhibitor design for the study, utilized a machine learning-powered protein-design tool and structural information to create a mini-protein. This mini-protein was designed to disrupt the AMA1-RON contact and blocked parasites from invading red blood cells in a dose-dependent manner. The designed mini-protein left already-infected cells unaffected. Kaxiras stated, "Once we could see the target in its real setting, designing something to block it became a tractable problem."

Why It Matters

Malaria kills approximately 600,000 people annually, primarily young children in sub-Saharan Africa. The malaria parasite is also developing resistance to frontline drugs. The Columbia University team's work provides a detailed understanding of how the parasite invades red blood cells. The development of a mini-protein that blocks this invasion mechanism offers a potential new approach for antimalarial therapies. This proof of concept requires further refinement before human testing.