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Phospholipid scramblases: An overview

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Abstract

Phospholipid scramblases are a group of homologous proteins that are conserved in all eukaryotic organisms. They are believed to be involved in destroying plasma membrane phospholipid asymmetry at critical cellular events like cell activation, injury and apoptosis. However, a detailed mechanism of phospholipid scrambling still awaits a proper understanding. The most studied member of this family, phospholipid scramblase 1 (PLSCR1) (a 37 kDa protein), is involved in rapid Ca2+ dependent transbilayer redistribution of plasma membrane phospholipids. Recently the function of PLSCR1 as a phospholipids translocator has been challenged and evidences suggest that PLSCR1 acts as signaling molecule. It has been shown to be involved in protein phosphorylation and as a potential activator of genes in response to interferon and other cytokines. Interferon induced rapid biosynthesis of PLSCR1 targets some of the protein into the nucleus, where it binds to the promoter region of inositol 1,4,5-triphosphate (IP3) receptor type 1 (IP3R1) gene and induces its expression. Palmitoylation of PLSCR1 acts as a switch, controlling its localization either to the PM or inside the nucleus. In the present review, we discuss the current understanding of PLSCR1 in relation to its trafficking, localization and signaling functions.

Section snippets

PLSCR homologues

In humans, PL scramblases (PLSCRs) constitute a family of four homologous proteins which are named as hPLSCR1–hPLSCR4 [19]. The predicted open reading frames of hPLSCR2 (224 aa), hPLSCR3 (295 aa) and hPLSCR4 (329 aa) show 59%, 47% and 46% homology, respectively, to hPLSCR1 [19]. PLSCR1, PLSCR2 and PLSCR4 are closely clustered on the small arm of chromosome 3 (3q23), whereas PLSCR3 is localized to chromosome 17. While hPLSCR1, 3 and 4 are expressed in a variety of tissues with few exceptions,

Biological role of scramblases

Biological functions of all identified members of the scramblase family are not yet completely understood. Recent work on this novel group of proteins has revealed more insight about the subcellular localization and functions of PLSCR1 and PLSCR3. In spite of a remarkable degree of homology to PLSCR1 and 3, subcellular localization and the biological functions of PLSCR2 and 4 are yet to be determined.

Methods for measurement of PL scrambling under different conditions

Redistribution of plasma membrane PLs is triggered by increased cytosolic Ca2+[18], [27]. However, the exact molecular mechanism of Ca2+ dependent PL redistribution is largely unknown. In vitro assays for scramblase using artificial lipid bilayers have provided some insights into the PL scrambling phenomenon. Most of the assay methods use fluorescent tagged PL analogues (e.g. NBD-PC, NBD-PS) to measure scramblase activity. These reporter molecules are randomly incorporated into both leaflets of

Modulation of PL scrambling activity by sulfhydryl (–SH) modifying agents

Scramblases are cysteine rich proteins, possessing many cysteinyl sulfhydryl (–SH) groups that are prone to sulfhydryl modifications [17]. While the exact regulatory mechanism of PL scrambling across the PM is unknown, scrambling activity of the most studied member of scramblase family, PLSCR1 all by itself is doubtful. Though it is well understood that increased cytosolic Ca2+ is a key regulatory factor triggering the scrambling activity in the erythrocyte membranes the actual changes in the

Palmitoylation and localization of PLSCR1

Palmitoylation is an essential and reversible post translational modification observed in many eukaryotic peripheral membrane proteins like the Src family kinases, Ras and the alpha subunit of heterotrimeric G proteins that need a loose attachment to the membranes [84], [85], [86], [87]. hPLSCR1 is palmitoylated within a cytoplasmic cysteine-palmitoylation site [184CCCPCC189] that is essential for PL scrambling activity of the protein [26], [88]. Palmitoylation of hPLSCR1 has been proposed to

Signaling functions of PLSCR1

Involvement of PLSCR1 in protein–protein interaction is becoming more evident from recent studies. In 2001, an immunoglobulin E (IgE) type I (FcεRI) dependent tyrosine phosphorylation of PLSCR1 in rat mast cells was identified [97], [98]. This showed PLSCR1 to be a new effector of mast cell signaling by an immuno receptor. However, the exact mechanism of mast cell signaling by PLSCR1 remains elusive. Multiple proline rich motifs (PXXP and PPXY) in the N-terminal domain show PLSCR1 to be a

Conclusion and future perspectives

In summary, previously identified PLSCR1 (37 kDa) may not be a true PL scramblase by itself, as the protein isolated from erythrocytes of Scott patients is normal and functionally active. In addition, its molecular weight is too small when compared to other membrane transporters to act as an efficient translocator of membrane lipids. Further, a very slow rate of PL scrambling by PLSCR1 when reconstituted into artificial lipid bilayers, a lack of correlation between surface exposure of PS and

Acknowledgment

Authors acknowledge Mrs. Jayashree for critical reading of the manuscript.

References (118)

  • O.C. Martin et al.

    J. Biol. Chem.

    (1987)
  • A.J. Smith et al.

    FEBS Lett.

    (1994)
  • D. Kamp et al.

    Biochim. Biophys. Acta

    (1998)
  • W.R. Bishop et al.

    Cell

    (1985)
  • A.J. Schroit et al.

    Biochim. Biophys. Acta

    (1991)
  • F. Basse et al.

    J. Biol. Chem.

    (1996)
  • T. Wiedmer et al.

    Biochim. Biophys. Acta

    (2000)
  • M.H. Chen et al.

    J. Biochem.

    (2005)
  • Q. Zhou et al.

    J. Biol. Chem.

    (2005)
  • C. Notredame et al.

    J. Mol. Biol.

    (2000)
  • J.B. McMillin et al.

    Biochim. Biophys. Acta

    (2002)
  • D.R. Green et al.

    Cancer Cell

    (2002)
  • T. Kuwana et al.

    Cell

    (2002)
  • J.S. Savill et al.

    Immunol. Today

    (1993)
  • Q. Zhou et al.

    Blood

    (2002)
  • E.M. Bevers et al.

    Biochim. Biophys. Acta

    (1983)
  • E.M. Bevers et al.

    Blood Rev.

    (1991)
  • T. Wiedmer et al.

    Blood

    (1986)
  • G.E. Gilbert et al.

    J. Biol. Chem.

    (1991)
  • P. Thiagarajan et al.

    J. Biol. Chem.

    (1991)
  • R.F.A. Zwaal et al.

    Biochim. Biophys. Acta

    (2004)
  • J.P. Miletich et al.

    Blood

    (1979)
  • Q. Zhou et al.

    J. Biol. Chem.

    (1997)
  • J. Zhao et al.

    J. Biol. Chem.

    (1998)
  • B. Fadeel et al.

    Biochem. Biophys. Res. Commun.

    (1999)
  • K. Eisele et al.

    Toxicol. Appl. Pharmacol.

    (2006)
  • A. Akel et al.

    Eur. J. Pharmacol.

    (2006)
  • C.W.M. Haest et al.

    Biochim. Biophys. Acta

    (1981)
  • Y.Y. Tyurina et al.

    J. Biol. Chem.

    (2007)
  • D.W. Martin et al.

    J. Biol. Chem.

    (1995)
  • F.A. Kuypers et al.

    Blood

    (1996)
  • B.L. Wood et al.

    Blood

    (1996)
  • P.F. Devaux et al.

    Chem. Phys. Lipids

    (1994)
  • R.P. Hebbel

    Blood

    (1991)
  • G. Ermak et al.

    Mol. Immunol.

    (2002)
  • K.C. Zimmermann et al.

    Pharmacol. Ther.

    (2001)
  • M.D. Resh

    Cell. Signal.

    (1996)
  • M.D. Resh

    Biochim. Biophys. Acta

    (1999)
  • S.C. Frasch et al.

    J. Biol. Chem.

    (2004)
  • C. Pastorelli et al.

    J. Biol. Chem.

    (2001)
  • J. Sun et al.

    J. Biol. Chem.

    (2001)
  • S. Kametaka et al.

    J. Biol. Chem.

    (2003)
  • A.K. Menon

    Trends Cell Biol.

    (1995)
  • M.A. Kol et al.

    Biochemistry

    (2004)
  • A. Zachowski

    Biochem. J.

    (1993)
  • T. Pomorski et al.

    J. Cell Sci.

    (2004)
  • E.M. Bevers et al.

    Biol. Chem.

    (1998)
  • H. Sprong et al.

    Nature

    (2001)
  • M. Seigneuret et al.

    Proc. Natl. Acad. Sci. USA

    (1984)
  • T. Pomorski et al.

    Biochemistry

    (1999)
  • Cited by (0)

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