The C-terminal transmembrane domain of human phospholipid scramblase 1 is essential for the protein flip-flop activity and Ca2+-binding

Sánchez-Magraner, Lissete; Posada, Itziar M. D.; Andraka, Nagore; Contreras, F.‐Xabier; Viguera, Ana Rosa; Guérin, Diego M. A.; Arrondo, José Luis R.; Monaco, Hugo L.; Goñi, Félix M.

doi:10.1007/s00232-013-9619-7

Cited by 16 publications

(14 citation statements)

References 38 publications

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“…The localization of PLSCR1 is directly correlated with its function. Because it was initially identified as plasma membrane protein, its role in regulating the movement of plasma membrane phospholipids was intensively studied [ 22 , 47 , 48 ]. Moreover, cell surface-localized PLSCR1 can bind to the envelope proteins E1 and E2 of HCV and serve as an attachment factor for HCV entry [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Phospholipid scramblase 1 interacts with influenza A virus NP, impairing its nuclear import and thereby suppressing virus replication

et al. 2018

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Transcription and replication of the influenza A virus (IAV) genome occur in the nucleus of infected cells and are carried out by the viral ribonucleoprotein complex (vRNP). As a major component of the vRNP complex, the viral nucleoprotein (NP) mediates the nuclear import of the vRNP complex via its nuclear localization signals (NLSs). Clearly, an effective way for the host to antagonize IAV infection would be by targeting vRNP nuclear import. Here, we identified phospholipid scramblase 1 (PLSCR1) as a binding partner of NP by using a yeast two-hybrid (Y2H) screen. The interaction between NP and PLSCR1 in mammalian cells was demonstrated by using co-immunoprecipitation and pull-down assays. We found that the stable overexpression of PLSCR1 suppressed the nuclear import of NP, hindered the virus life cycle, and significantly inhibited the replication of various influenza subtypes. In contrast, siRNA knockdown or CRISPR/Cas9 knockout of PLSCR1 increased virus propagation. Further analysis indicated that the inhibitory effect of PLSCR1 on the nuclear import of NP was not caused by affecting the phosphorylation status of NP or by stimulating the interferon (IFN) pathways. Instead, PLSCR1 was found to form a trimeric complex with NP and members of the importin α family, which inhibited the incorporation of importin β, a key mediator of the classical nuclear import pathway, into the complex, thus impairing the nuclear import of NP and suppressing virus replication. Our results demonstrate that PLSCR1 negatively regulates virus replication by interacting with NP in the cytoplasm and preventing its nuclear import.

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Section: Discussionmentioning

confidence: 99%

Phospholipid scramblase 1 interacts with influenza A virus NP, impairing its nuclear import and thereby suppressing virus replication

et al. 2018

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“…Investigations into the nature of the C-terminal transmembrane helix of hPLSCR1 confirmed its function in inserting the protein into the bilayer of reconstituted liposomes and revealed an additional role in coordinating the metal ion, thus influencing scramblase activity (21,41). Two cholesterolbinding sites, composed of Ala 291 , Phe 298 , Leu 299 and Leu 299 , Phe 302 , Glu 306 , respectively have also been identified and proposed to stabilise the C-terminal transmembrane helix in the phospholipid bilayer.…”

Section: Pfplscr Is Not Essential For Erythrocyte Invasion and Asexuamentioning

confidence: 90%

Identification and characterisation of a phospholipid scramblase in the malaria parasite Plasmodium falciparum

Haase

Condron

Miller

et al. 2020

Preprint

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Recent studies highlight the emerging role of lipids as important messengers in malaria parasite biology. In an attempt to identify interacting proteins and regulators of these dynamic and versatile molecules, we hypothesised the involvement of phospholipid translocases and their substrates in the infection of the host erythrocyte by the malaria parasite Plasmodium spp. Here, using a data base mining approach, we have identified a putative phospholipid (PL) scramblase in P. falciparum (PfPLSCR) that is conserved across the genus and in closely related unicellular algae. By reconstituting recombinant PfPLSCR into liposomes, we demonstrate metal ion dependent PL translocase activity and substrate preference, confirming PfPLSCR as a bona fide scramblase. We confirm that PfPLSCR is expressed during asexual and sexual parasite development, localising to different membranous compartments of the parasite throughout the intra-erythrocytic life cycle. Two different gene knockout approaches, however, suggest that PfPLSCR is not essential for erythrocyte invasion and asexual parasite development, pointing towards a possible role in other stages of the parasite life cycle.

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“…Several studies have demonstrated an increase in phospholipid scrambling in the presence of calcium [128, 129, 138]. Recent work confirms the importance of the C-terminal alpha helix for both calcium binding and scrambling activity [121, 139]. It is hypothesized that calcium binding is followed by a conformational change and perhaps self-aggregation [131, 137, 138].…”

Section: The Response Of Phospholipid Scramblase 1 To Hypoxiamentioning

confidence: 99%

Membrane lipid interactions in intestinal ischemia/reperfusion-induced Injury

Slone

Fleming

2014

Clinical Immunology

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Ischemia, lack of blood flow, and reperfusion, return of blood flow, is a common phenomenon affecting millions of Americans each year. Roughly 30,000 Americans per year experience intestinal ischemia-reperfusion (IR), which is associated with a high mortality rate. Previous studies of the intestine established a role for neutrophils, eicosanoids, the complement system and naturally occurring antibodies in IR-induced pathology. Furthermore, data indicate involvement of a lipid or lipid-like moiety in mediating IR-induced damage. It has been proposed that exposure of neo-antigens are recognized by antibodies, triggering action of the complement cascade. While it is evident that the pathophysiology of IR-induced injury is complex and multi-factorial, we focus this review on the involvement of eicosanoids, phospholipids and neo-antigens in the early pathogenesis. Lipid changes occurring in response to IR, neo-antigens exposed and the role of a phospholipid transporter, phospholipid scramblase 1 will be discussed.

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The C-terminal transmembrane domain of human phospholipid scramblase 1 is essential for the protein flip-flop activity and Ca2+-binding

Cited by 16 publications

References 38 publications

Phospholipid scramblase 1 interacts with influenza A virus NP, impairing its nuclear import and thereby suppressing virus replication

Phospholipid scramblase 1 interacts with influenza A virus NP, impairing its nuclear import and thereby suppressing virus replication

Identification and characterisation of a phospholipid scramblase in the malaria parasite Plasmodium falciparum

Membrane lipid interactions in intestinal ischemia/reperfusion-induced Injury

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