Structure of the Plasmodium-interspersed repeat proteins of the malaria parasite

Area of Science:

• Parasitology
• Structural Biology
• Genomics

Background:

• Malaria, caused by Plasmodium parasites, leads to severe symptoms due to parasite replication in blood cells.
• Variant surface proteins on infected cells, including Plasmodium-interspersed repeat (PIR) proteins, are crucial but poorly understood.
• The classification of PIR proteins and their relationship to Plasmodium falciparum proteins like RIFINs and STEVORs remain controversial.

Purpose of the Study:

• To determine the structure of the Plasmodium chabaudi PIR protein's extracellular domain.
• To establish a structure-guided definition for the Plasmodium-interspersed repeat (PIR) protein superfamily.
• To clarify the evolutionary relationships and membership of PIR proteins, including RIFINs and STEVORs.

Main Methods:

• X-ray crystallography to determine the extracellular domain structure of a Plasmodium chabaudi PIR protein.
• Structure-guided sequence analysis to identify conserved folds across different Plasmodium species.
• Molecular modeling to assess protein relationships and evolutionary history.

Main Results:

• The study reveals the conserved three-dimensional fold of the extracellular domain of Plasmodium-interspersed repeat (PIR) proteins.
• This fold is present in PIR proteins from both rodent and human malaria parasites.
• Structure and sequence analyses demonstrate that RIFINs and STEVORs are distinct protein families and not members of the PIR superfamily.

Conclusions:

• A definitive, structure-guided definition of the Plasmodium-interspersed repeat (PIR) protein family is established.
• RIFINs and STEVORs are confirmed as separate from the PIR superfamily.
• This work provides a molecular framework for understanding PIR protein evolution and function in malaria parasites.