Regulation and Essentiality of the StAR-related Lipid Transfer (START) Domain-containing Phospholipid Transfer Protein PFA0210c in Malaria Parasites.
StAR-related lipid transfer (START) domains are phospholipid- or sterol-binding modules that are present in many proteins. START domain-containing proteins (START proteins) play important functions in eukaryotic cells, including the redistribution of phospholipids to subcellular compartments and delivering sterols to the mitochondrion for steroid synthesis. How the activity of the START domain is regulated remains unknown for most of these proteins. The Plasmodium falciparum START protein PFA0210c (PF3D7_0104200) is a broad-spectrum phospholipid transfer protein that is conserved in all sequenced Plasmodium species and is most closely related to the mammalian START proteins STARD2 and STARD7. PFA0210c is unusual in that it contains a signal sequence and a PEXEL export motif that together mediate transfer of the protein from the parasite to the host erythrocyte. The protein also contains a C-terminal extension, which is very uncommon among mammalian START proteins. Whereas the biochemical properties of PFA0210c have been characterized, the function of the protein remains unknown. Here, we provide evidence that the unusual C-terminal extension negatively regulates phospholipid transfer activity. Furthermore, we use the genetically tractable Plasmodium knowlesi model and recently developed genetic technology in P. falciparum to show that the protein is essential for growth of the parasite during the clinically relevant asexual blood stage life cycle. Finally, we show that the regulation of phospholipid transfer by PFA0210c is required in vivo, and we identify a potential second regulatory domain. These findings provide insight into a novel mechanism of regulation of phospholipid transfer in vivo and may have important implications for the interaction of the malaria parasite with its host cell.
From the The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA and.
Ross J
RJ
Hill
From the The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA and.
Alessa
A
Ringel
From the The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA and.
Ellen
E
Knuepfer
the Departments of Infection and Immunity and.
Robert W
RW
Moon
From the The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA and.|Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, London WC1E 7HT, United Kingdom.
Michael J
MJ
Blackman
From the The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA and christiaan.vanOoij@crick.ac.uk.
Christiaan
C
van Ooij
D001693:Biological Transport, Active / Q000502:physiology; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D010743:Phospholipids / Q000235:genetics / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism*; D016790:Plasmodium knowlesi / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*
D049294:Phospholipid Transfer Proteins; D010743:Phospholipids; D015800:Protozoan Proteins
lipid transport; malaria; parasitology; phospholipid; plasmodium
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