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Regulation and Essentiality of the Star-Related Lipid Transfer (START

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Regulation and Essentiality of the Star-Related Lipid Transfer (START crossmark THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 291, NO. 46, pp. 24280–24292, November 11, 2016 Author’s Choice © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. Regulation and Essentiality of the StAR-related Lipid Transfer (START) Domain-containing Phospholipid Transfer Protein PFA0210c in Malaria Parasites* Received for publication, May 26, 2016, and in revised form, September 23, 2016 Published, JBC Papers in Press, October 2, 2016, DOI 10.1074/jbc.M116.740506 Ross J. Hill‡1, Alessa Ringel‡2, Ellen Knuepfer‡, Robert W. Moon§, Michael J. Blackman‡¶, and Christiaan van Ooij‡3 From the ‡The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA and the Departments of §Infection and Immunity and ¶Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, London WC1E 7HT, United Kingdom Downloaded from Edited by George Carman StAR-related lipid transfer (START) domains are phospho- Phospholipid transfer proteins play important roles in the lipid- or sterol-binding modules that are present in many pro- trafficking of phospholipids within eukaryotic cells (1). One teins. START domain-containing proteins (START proteins) subset of phospholipid transfer proteins is represented by a http://www.jbc.org/ play important functions in eukaryotic cells, including the redis- group of proteins containing a StAR-related (START)4 lipid- tribution of phospholipids to subcellular compartments and transfer domain, which mediates the binding to lipids or sterols delivering sterols to the mitochondrion for steroid synthesis. and can promote their transfer between membranes. Although How the activity of the START domain is regulated remains sequence similarity between different START domains can be unknown for most of these proteins. The Plasmodium falcipa- very low, all are characterized by a specific fold consisting of at LONDON SCH OF HYGIENE & TROPICAL MEDICINE on March 5, 2018 rum START protein PFA0210c (PF3D7_0104200) is a broad- four ␣-helices and a nine-stranded twisted antiparallel ␤-sheet spectrum phospholipid transfer protein that is conserved in all that together form a cavity in which a hydrophobic phospho- sequenced Plasmodium species and is most closely related to the lipid or sterol is held (2, 3). The human genome encodes 15 mammalian START proteins STARD2 and STARD7. PFA0210c different START domain-containing proteins (START pro- is unusual in that it contains a signal sequence and a PEXEL teins) that can be categorized into five different groups based on export motif that together mediate transfer of the protein from the bound ligand specificity and the presence of additional the parasite to the host erythrocyte. The protein also contains a functional domains (Table 1) (4–7). The roles of the different C-terminal extension, which is very uncommon among mam- START proteins are in most cases not well understood, malian START proteins. Whereas the biochemical properties of although mutations in genes encoding START proteins have PFA0210c have been characterized, the function of the protein been linked with various diseases (5, 8). It is clear from genetic remains unknown. Here, we provide evidence that the unusual experiments in mice that at least two of the murine START C-terminal extension negatively regulates phospholipid trans- proteins, STARD11 and STARD12, are essential (9, 10). The fer activity. Furthermore, we use the genetically tractable Plas- best characterized human START proteins are STARD2, modium knowlesi model and recently developed genetic tech- STARD7, and STARD10, which all transfer phosphatidylcho- nology in P. falciparum to show that the protein is essential for line (and additionally phosphatidylethanolamine in the case of growth of the parasite during the clinically relevant asexual STARD10) (11–13). Although their exact functions are unclear, blood stage life cycle. Finally, we show that the regulation of the proteins appear to have a role in the transfer of phospholip- phospholipid transfer by PFA0210c is required in vivo, and we ids from the endoplasmic reticulum to mitochondria and pos- identify a potential second regulatory domain. These findings sibly the plasma membrane (14, 15). What is also not under- provide insight into a novel mechanism of regulation of phos- stood is whether and how the transfer of phospholipids by these pholipid transfer in vivo and may have important implications proteins is regulated. Some of the START proteins consist of for the interaction of the malaria parasite with its host cell. little more than the START domain itself, whereas others con- tain additional domains, such as thioesterase or Rho-GAP domains (Table 1). Some START proteins, including STARD2 * This work was supported in part by Wellcome Trust Career Re-Entry Fellow- and STARD12, have been shown to interact with other proteins ship 095836/Z/1/Z (to C. v. O.), UK Medical Research Council Grant (16, 17), which may provide a mechanism of regulating phos- FC001043, Cancer Research UK Grant FC001043, and Wellcome Trust Grant FC001043. The authors declare that they have no conflicts of pholipid transfer activity, or conversely, to allow the START interest with the contents of this article. protein to regulate the interacting protein. In the case of Author’s Choice—Final version free via Creative Commons CC-BY license. STARD10, phosphorylation of a residue in a C-terminal exten- 1 Recipient of an MRC Sandwich studentship. Present address: Division of sion has been shown to regulate transfer activity (18). Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Ave., Cambridge CB2 0QH, United Kingdom. Most members of the genus Plasmodium, which are the obli- 2 Present address: Westfälische Wilhelms-Universität Münster, 48149 Mün- gate intracellular parasites that cause malaria, encode four START ster, Germany. proteins (19). These include a putative orthologue of STARD2 3 To whom correspondence should be addressed: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA, United King- dom. Tel.: 44-208-816-2124; E-mail: [email protected]. 4 The abbreviation used is: START, StAR-related lipid-transfer. 24280 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 291•NUMBER 46•NOVEMBER 11, 2016 Regulation of a Phospholipid Transfer Protein (phosphatidylcholine transfer protein; PF3D7_1351000) and an mechanism of regulating phospholipid transfer and show that uncharacterized protein (PF3D7_0911100) with a putative phospholipid transfer is an essential and regulated process in cyclin-dependent serine/threonine kinase domain that also Plasmodium parasites. contains a START domain at its C terminus. The third START protein (PF3D7_1463500) displays similarity to StarD3 Results (MLN64), a cholesterol transfer protein (20). Interestingly, in PFA0210c and Its Orthologue in P. knowlesi Are Essential— rodent malaria parasites this protein forms part of the large PFA0210c was initially identified as a conserved exported pro- Fam A family, whereas in non-rodent malaria parasites, only tein (29). We subsequently showed that PFA0210c as well as its one family member is present (21–23). The best character- orthologues in the simian and human malaria pathogen ized START protein in Plasmodium spp. is the exported P. knowlesi (PKH_020910 or PKNH_0209300) and the broad specificity phospholipid transfer protein PFA0210c rodent parasite Plasmodium chabaudi (PCHAS_020730 or (PF3D7_0104200). PSI-BLAST analysis shows that PFA0210c PCHAS_0207300) are phospholipid transfer proteins that can Downloaded from is most closely related to STARD7, whereas structure predic- transfer a broad range of phospholipids in vitro (24). All three tion reveals that the highest similarity is to human phosphati- proteins contain a signal sequence and a predicted PEXEL dylcholine transfer protein STARD2 (24). motif that directs export from the parasite into the host eryth- Phospholipid transfer proteins in Plasmodium are of partic- rocyte (Fig. 1A) (29–31). The proteins are characterized by a ular interest as one of the most striking changes induced by the poorly conserved N-terminal region, a START domain that is parasite in the host erythrocyte, the site of replication of the required for the phospholipid transfer activity (24), and a C-ter- http://www.jbc.org/ parasite during the clinical stage of the disease, is the formation minal extension of ϳ84 amino acid residues (Fig. 1B). To gain of a large exomembrane system (25). This consists of several further insight into the function of this protein, we used the different, most likely unconnected, membranous compart- recently developed P. knowlesi A.1-H.1 strain that has been ments that have various functions within the cell. One of these adapted to in vitro growth in human erythrocytes (32) to membranous compartments is the parasitophorous vacuole attempt to generate a mutant that lacks the gene encoding at LONDON SCH OF HYGIENE & TROPICAL MEDICINE on March 5, 2018 membrane that surrounds the parasite during the entire intra- PKH_020910. The P. knowlesi model is highly genetically trac- erythrocytic life cycle and that separates the parasite from the table, allowing for rapid gene modification by homologous erythrocyte cytosol. Another group of membranous compart- recombination. We first confirmed that PKH_020910 is ments is the Maurer’s clefts, small vesicles that are important expressed in in vitro culture by immunoblotting. Full-length for the transfer
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