Malaria Parasite Translocon Structure and Mechanism of Effector Export

The putative Plasmodium Translocon of Exported Proteins (PTEX) is essential for transport of malarial effector proteins across a parasite-encasing vacuolar membrane into host erythrocytes, but the mechanism of this process remains unknown. Here we show PTEX is a bona fide translocon by determining near-atomic resolution cryoEM structures of the endogenous PTEX core complex of EXP2, PTEX150 and HSP101, isolated from Plasmodium falciparum in the engaged and resetting states of endogenous cargo translocation with CRISPR/Cas9-engineered epitope tags. EXP2 and PTEX150 interdigitate to form a static, funnel-shaped pseudo-sevenfold symmetric protein-conducting channel spanning the vacuolar membrane. Tethered above this funnel, the spiral-shaped AAA+ HSP101 hexamer undergoes a dramatic compaction that allows three of six tyrosine-bearing pore loops lining the HSP101 channel to dissociate from the cargo, resetting the translocon for the next threading cycle. Our work reveals the mechanism of P. falciparum effector export, enabling structure-based design of drugs targeting this unique translocon.