Snapshots reveal key molecular machine in tropical parasites at near-atomic resolution

A recent study conducted by researchers at the University of Liège and Rockefeller University has provided near-atomic resolution details of a crucial molecular machine in tropical parasites. This machine, called the trans-spliceosome, is essential for the survival of trypanosomatid parasites which cause diseases like leishmaniasis, sleeping sickness and Chagas disease in humans, animals and plants.

Trypanosomatids use a unique form of RNA splicing that inserts a short RNA sequence, known as the Spliced Leader (SL) RNA, into messenger RNA at the 5 end. This process is different to conventional intron splicing seen in human cells. The trans-spliceosome machine is a complex molecular factory and despite being discovered nearly 40 years ago, the specifics of how it works have remained unclear.

To elucidate the structure and function of this machine, the researchers employed a technique called cryogenic electron microscopy (cryo-EM), which captures high-resolution images of the parasite's molecular components. These images revealed two distinct stages of the trans-spliceosome's activity - when the SL RNA binds to the messenger RNA and the state immediately following this reaction.

The resulting detailed structures revealed the organization of the machine's core, the positioning of RNA molecules during the reaction, and the roles of several parasite-specific proteins absent in human cells.

The findings provide new insights into the evolutionary history of eukaryotic molecular machinery and open up possibilities for developing selective inhibitors that can target the trans-spliceosome in trypanosomatids without affecting human cells. This could lead to new treatments for tropical diseases caused by these parasites.