Molecular Cloning of Human Plasma Membrane Phospholipid Scramblase

Zhou, Quansheng; Zhao, Jinmin; Stout, James G.; Luhm, Robert A.; Wiedmer, Therese; Sims, P.

doi:10.1074/jbc.272.29.18240

Cited by 375 publications

(191 citation statements)

References 19 publications

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“…16,36 A Ca 2+ -dependent lipid scrambling activity has been reconstituted in artificial lipid vesicles with proteins isolated from erythrocytes 37 and platelets, 38 and the protein from erythrocytes responsible for this activity cloned. 39 However, the activity of the reconstituted protein is very low and other proteins may also be involved in PS externalization. 39,40 Although it appears that CED-7/ABC-1 is involved in PS externalization, 27 ATP does not seem to be required for the dissipation of membrane phospholipid asymmetry, 41 leaving open the question of what that involvement might be.…”

Section: Discussionmentioning

confidence: 99%

“…39 However, the activity of the reconstituted protein is very low and other proteins may also be involved in PS externalization. 39,40 Although it appears that CED-7/ABC-1 is involved in PS externalization, 27 ATP does not seem to be required for the dissipation of membrane phospholipid asymmetry, 41 leaving open the question of what that involvement might be.…”

Section: Discussionmentioning

confidence: 99%

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Surface expression of phosphatidylserine on macrophages is required for phagocytosis of apoptotic thymocytes

2000

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Cells generally maintain an asymmetric distribution of phospholipids across the plasma membrane bilayer, restricting the phospholipid, phosphatidylserine (PS), to the inner leaflet of the plasma membrane. When cells undergo apoptosis, this asymmetric transbilayer distribution is lost, bringing PS to the surface where it acts as a signal for engulfment by phagocytes. The fluorescent dye merocyanine 540 specifically stains the plasma membrane of apoptotic cells which have lost their asymmetric distribution of phospholipids. However, it also stains non-apoptotic macrophages, suggesting that phospholipid asymmetry may not be maintained in these cells, and thus that they may express PS on their surface. Here, the PS-binding protein, annexin V, was used to show that in fact normal macrophages do express PS on their surface. Furthermore, pre-treating macrophages with annexin V was found to inhibit phagocytosis of apoptotic thymocytes and thymocytes on which PS expression was artificially induced, but did not inhibit phagocytosis of latex beads or Fc receptor-mediated phagocytosis of opsonized erythrocytes. These results indicate that PS is constitutively expressed on the surface of macrophages and is functionally significant for the phagocytosis of PS-expressing target cells. Cell Death and Differentiation (2000) 7, 645 ± 653.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Surface expression of phosphatidylserine on macrophages is required for phagocytosis of apoptotic thymocytes

2000

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“…7 Interestingly, this protein is present in a variety of tissues and cells, showing highest levels in platelets, and correlates with their activity upon activation. 8 A variety of agents (hemin, retinoids, phorbol esters, transforming growth factor-b, dimethylsulfoxide, and butyrate) can induce myeloid cells to differentiate in vitro, a phenomenon that is usually associated with concomitant apoptosis. Although this may also be true for normal erythroid progenitors, it seems likely that cell cycle deregulation in transformed cell lines used to model this process in vitro, makes them more resistant and susceptible to differentiation and apoptosis, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Elevation of intracellular Ca 2+ levels can trigger PS exposure by activation of a Ca 2+ -dependent membrane protein that randomizes phospholipids across the membrane bilayer. 7,8 This`scramblase' is a membrane-spanning 37 kDa proline-rich polypeptide that is present in a variety of hematologic and nonhematologic cells. 8 Its activation, combined with the Ca 2+ -dependent inactivation of aminophospholipid translocase, has also been implicated in apoptosis-dependent PS exposure.…”

Section: Introductionmentioning

confidence: 99%

“…7,8 This`scramblase' is a membrane-spanning 37 kDa proline-rich polypeptide that is present in a variety of hematologic and nonhematologic cells. 8 Its activation, combined with the Ca 2+ -dependent inactivation of aminophospholipid translocase, has also been implicated in apoptosis-dependent PS exposure. 9 ± 11 Ca 2+ -mediated PS exposure may also involve activation of calpain, which like caspases, can cleave fodrin.…”

Section: Introductionmentioning

confidence: 99%

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Phosphatidylserine externalization during differentiation-triggered apoptosis of erythroleukemic cells

et al. 1999

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K562 erythroleukemia cells undergo apoptosis when induced to differentiate along the erythroid lineage with hemin. This event, characterized by DNA fragmentation, correlated with downregulation of the survival protein, BCL-x L , and decrease in mitochondrial transmembrane potential (DC m ) that ultimately resulted in cell death. Reorientation of phosphatidylserine (PS) from the cells inner-to-outer plasma membrane leaflet and inhibition of the aminophospholipid translocase was observed upon hemin-treatment. Constitutive expression of BCL-2 did not inhibit hemin-induced alterations in lipid asymmetry or decrease in DC m , and only moderately prevented DNA fragmentation. BCL-2, on the other hand, effectively inhibited actinomycin D-induced DNA fragmentation, the appearance of PS at the cells outer leaflet and the decrease in DC m . The caspase inhibitor, z.VAD.fmk, blocked DNA fragmentation by both hemin and actinomycin D, but inhibited PS externalization only in the actinomycin D-treated cells. These results suggest that, unlike pharmacologicallyinduced apoptosis, PS externalization triggered by differentiation-induced apoptosis occurs by a mechanism that is associated with a decrease in DC m , but independent of BCL-2 and caspases.

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Topological characterization of the mitochondrial phospholipid scramblase 3

Luévano‐Martínez

Kowaltowski

2017

FEBS Letters

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Scramblases redistribute phospholipids in biological membranes. Phospholipid scramblase 3 (PLSCR3), which is located in mitochondria, has been reported to be involved in cardiolipin distribution from the inner to the outer membrane, thus regulating cellular processes such as apoptosis or mitophagy. However, the localization and topology of this protein has not been convincingly addressed to support a role in intermembrane phospholipid transfer. Here, we studied PLSCR3 topology within mitochondria. We show that PLSCR3 inserts in the inner membrane (IM) via its C-terminal transmembrane helix, whereas its N-terminal portion is oriented toward the intermembrane space where it is activated by calcium. Our results suggest that PLSCR3, via its C-terminal transmembrane domain, participates in the bidirectional movement of phospholipids within the IM.

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Molecular Cloning of Human Plasma Membrane Phospholipid Scramblase

Cited by 375 publications

References 19 publications

Surface expression of phosphatidylserine on macrophages is required for phagocytosis of apoptotic thymocytes

Surface expression of phosphatidylserine on macrophages is required for phagocytosis of apoptotic thymocytes

Phosphatidylserine externalization during differentiation-triggered apoptosis of erythroleukemic cells

Topological characterization of the mitochondrial phospholipid scramblase 3

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