MinireviewPhospholipid scramblases: An overview
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.
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