Phospholipid scramblases: An overview

Sahu, Santosh Kumar; Gummadi, Sathyanarayana N.; Manoj, Narayanan; Aradhyam, Gopala Krishna

doi:10.1016/j.abb.2007.04.002

Cited by 199 publications

(195 citation statements)

References 110 publications

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“…During apoptosis or cell injury, a rise in intracellular Ca 2+ levels triggers two concomitant events that disrupt this normal arrangement: the inhibition of aminophospholipid translocase and the stimulation of scramblases, enzymes that facilitate the transbilayer randomization of phosphatidylserine 49,50 . In addition to membrane reshuffling, Ca 2+ also stimulates cytosolic enzymes that catalyse the synthesis of this phospholipid 51 .…”

Section: Flippasementioning

confidence: 99%

A neuroscientist's guide to lipidomics

2007

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| Nerve cells mould the lipid fabric of their membranes to ease vesicle fusion, regulate ion fluxes and create specialized microenvironments that contribute to cellular communication. The chemical diversity of membrane lipids controls protein traffic, facilitates recognition between cells and leads to the production of hundreds of molecules that carry information both within and across cells. With so many roles, it is no wonder that lipids make up half of the human brain in dry weight. The objective of neural lipidomics is to understand how these molecules work together; this difficult task will greatly benefit from technical advances that might enable the testing of emerging hypotheses.

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Section: Flippasementioning

confidence: 99%

A neuroscientist's guide to lipidomics

2007

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“…Homology studies of PLSCRs reveal that hPLSCR2, -3, and -4 share 59, 47, and 46% similarity with hPLSCR1 (5). PLSCRs are multidomain-containing proteins where each domain has distinct functions that need to be elucidated.…”

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confidence: 99%

“…4 The unique feature of PM is the maintenance of membrane asymmetry by phosphatidylcholine and sphingomyelin, which are localized in the outer leaflet, whereas aminophospholipids such as phosphatidylserine (PS) and phosphatidylethanolamine are predominant in the inner leaflet of PM. This asymmetry is maintained by the concerted action of energy (ATP)-dependent phospholipid (PL) translocators, which include flippases and floppases (1)(2)(3)(4)(5). PM of eukaryotic cells is also equipped with a special class of PL translocators called human phospholipid scramblase 1(hPLSCR1).…”

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confidence: 99%

“…PLSCRs are multidomain-containing proteins where each domain has distinct functions that need to be elucidated. Major domains of PLSCRs include proline-rich domain (PRD), DNA binding motif, palmitoylation motif, nuclear localization signal, putative EF-hand like calcium binding motif, and C-terminal helix (CTH) (5). Except for hPLSCR2, members of scramblase family contain an N-terminal PRD that possesses PXXP and PPXY motifs via which they interact with multiple proteins (13)(14)(15)(16)(17).…”

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confidence: 99%

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N-terminal Proline-rich Domain Is Required for Scrambling Activity of Human Phospholipid Scramblases

Rayala¹,

Francis²,

Sivagnanam³

et al. 2014

Journal of Biological Chemistry

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Background:The role of PRD in scrambling of phospholipids by hPLSCR1 is not known. Results:The addition of PRD of hPLSCR1 to hPLSCR2 restored its PL scrambling activity, which in turn leads to aggregation of the protein. Conclusion: PRD is crucial for PL scrambling activity and could probably mediate its function by metal ion-dependent oligomerization. Significance: The results provide an insight in understanding the mechanism of scramblases.

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“…Recently, a three-dimensional model for PLSCR1 has been proposed, predicting that this protein is attached to the membrane only through palmitoylation, without the involvement of a transmembrane domain (47). We could not observe any PLSCR1 protein present on the membrane of HaCaT cells in FACS experiments, when stained with a polyclonal antibody against PLSCR1 or an antibody directed against the C terminus of PLSCR1 (aa 306 -318, which up to now was considered as the extracellular domain of PLSCR1) (23). Our studies do not support the above mentioned computational model in that we were able to show non-involvement of the palmitoylation in the membrane translocation (Fig.…”

Section: Discussionmentioning

confidence: 86%

Phospholipid Scramblase 1 Is Secreted by a Lipid Raft-dependent Pathway and Interacts with the Extracellular Matrix Protein 1 in the Dermal Epidermal Junction Zone of Human Skin

Merregaert¹,

Langen²,

Hansen

et al. 2010

Journal of Biological Chemistry

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We examined the interaction of ECM1 (extracellular matrix protein 1) using yeast two-hybrid screening and identified the type II transmembrane protein, PLSCR1 (phospholipid scramblase 1), as a binding partner. This interaction was then confirmed by in vitro and in vivo co-immunoprecipitation experiments, and additional pull-down experiments with GST-tagged ECM1a fragments localized this interaction to occur within the tandem repeat region of ECM1a. Furthermore, immunohistochemical staining revealed a partial overlap of ECM1 and PLSCR1 in human skin at the basal epidermal cell layer. Moreover, in human skin equivalents, both proteins are expressed at the basal membrane in a dermal fibroblast-dependent manner. Next, immunogold electron microscopy of ultrathin human skin sections showed that ECM1 and PLSCR1 co-localize in the extracellular matrix, and using antibodies against ECM1 or PLSCR1 cross-linked to magnetic immunobeads, we were able to demonstrate PLSCR1-ECM1 interaction in human skin extracts. Furthermore, whereas ECM1 is secreted by the endoplasmic/Golgi-dependent pathway, PLSCR1 release from HaCaT keratinocytes occurs via a lipid raft-dependent mechanism, and is deposited in the extracellular matrix. In summary, we here demonstrate that PLSCR1 interacts with the tandem repeat region of ECM1a in the dermal epidermal junction zone of human skin and provide for the first time experimental evidence that PLSCR1 is secreted by an unconventional secretion pathway. These data suggest that PLSCR1 is a multifunctional protein that can function both inside and outside of the cell and together with ECM1 may play a regulatory role in human skin.The human ECM1 gene (11 exons) is located on chromosome 1q21.2 (1, 2) and encodes four splice variants. ECM1a (without exon 5a) is expressed in basal keratinocytes, dermal blood vessels, and adnexal epithelia, including hair follicles and glands, whereas ECM1b, which lacks exon 7, is expressed in the spinous and granular layers of the epidermis (3-5). ECM1c was found in the basal layer of the epidermis (6), and a fourth splice variant results in a truncated protein of 57 amino acids (7). The ECM1 protein contains a 19-amino acid signal peptide followed by four domains: a cysteine-free N-terminal segment, two tandem repeats, and a C-terminal segment. The two tandem repeats and the C-terminal domain contain cysteines in a typical CC-(X 7-10 )C arrangement that is capable of forming protein double loops that could be involved in protein-protein interactions (1, 8). More recently, a rudimentary three-dimensional model divided the ECM1a protein into four distinct domains: an NH 2 -terminal domain forming ␣-helical structures, followed by three domains, whose amino acid sequences were highly comparable with the third domain of human serum albumin: SASDL2 (serum albumin subdomain-like 2), SASDL3, and SASDL4 (9).The function of ECM1 has not yet been elucidated in detail; however, it has been reported that ECM1 could act as a novel paracrine factor involved in the regulation of endocho...

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Phospholipid scramblases: An overview

Cited by 199 publications

References 110 publications

A neuroscientist's guide to lipidomics

A neuroscientist's guide to lipidomics

N-terminal Proline-rich Domain Is Required for Scrambling Activity of Human Phospholipid Scramblases

Phospholipid Scramblase 1 Is Secreted by a Lipid Raft-dependent Pathway and Interacts with the Extracellular Matrix Protein 1 in the Dermal Epidermal Junction Zone of Human Skin

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