Exposure of phosphatidylserine on the cell surface

Nagata, Shinji; Suzuki, Jun; Segawa, Katsumori; Fujii, Toshihiro

doi:10.1038/cdd.2016.7

Cited by 386 publications

(316 citation statements)

References 133 publications

(150 reference statements)

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“…Dissipation of this asymmetry in response to the elevation of cytoplasmic Ca 2+ concentration is a ubiquitous signaling mechanism critical for diverse cellular events including blood coagulation, bone mineralization, and cell-cell interaction (Fadok et al, 1992;Fadok et al, 2001;Sahu et al, 2007;Bratton and Henson, 2008;Sanyal and Menon, 2009;Bevers and Williamson, 2016;Nagata et al, 2016;Pomorski and Menon, 2016). Phospholipid scrambling is mediated by phospholipid scramblases, which harvest the energy of the phospholipid gradient to drive the nonspecific and bidirectional transport of phospholipids between leaflets.…”

Section: Introductionmentioning

confidence: 99%

Lipids and Ions Traverse the Membrane by the Same Physical Pathway in the nhTMEM16 Scramblase

Jiang

Hartzell

et al. 2018

Biophysical Journal

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From bacteria to mammals, different phospholipid species are segregated between the inner and outer leaflets of the plasma membrane by ATP-dependent lipid transporters. Disruption of this asymmetry by ATP-independent phospholipid scrambling is important in cellular signaling, but its mechanism remains incompletely understood. Using MD simulations coupled with experimental assays, we show that the surface hydrophilic transmembrane cavity exposed to the lipid bilayer on the fungal scramblase nhTMEM16 serves as the pathway for both lipid translocation and ion conduction across the membrane. Ca 2+ binding stimulates its open conformation by altering the structure of transmembrane helices that line the cavity. We have identified key amino acids necessary for phospholipid scrambling and validated the idea that ions permeate TMEM16 Cl -channels via a structurally homologous pathway by showing that mutation of two residues in the pore region of the TMEM16A Ca 2+ -activated Cl -channel convert it into a robust scramblase.

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Section: Introductionmentioning

confidence: 99%

Lipids and Ions Traverse the Membrane by the Same Physical Pathway in the nhTMEM16 Scramblase

Jiang

Hartzell

et al. 2018

Biophysical Journal

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“…ATP11A and ATP11C, members of the P4-type ATPase family, act as flippases at the plasma membrane in most cells (6,7). Two processes, flippase inactivation and scramblase activation, must occur to disrupt the asymmetrical phospholipid distribution and expose PtdSer on the cell surface (8).…”

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confidence: 99%

“…Ca 2+ -activated phospholipid scrambling is mediated by membrane proteins that belong to the transmembrane protein (TMEM)16 (also called ANO) family (8). Of 10 human TMEM16-family members, 5 are Ca 2+ -activated phospholipid scramblases at plasma membranes.…”

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confidence: 99%

“…Phospholipid scrambling and PtdSer exposure in apoptotic cells is mediated by another family of membrane proteins, the XK-related (Xkr) proteins (8). Of 10 human Xkr family members, Xkr8 (ubiquitously expressed) and Xkr4 and Xkr9 (expressed in specific tissues) are cleaved by caspase during apoptosis to expose PtdSer (14,15), but how the cleavage activates these Xkrs to scramble phospholipids is unknown.…”

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confidence: 99%

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Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure

Suzuki

Imanishi

Nagata

2016

Proc. Natl. Acad. Sci. U.S.A.

117

130

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Xk-related protein (Xkr) 8, a protein carrying 10 transmembrane regions, is essential for scrambling phospholipids during apoptosis. Here, we found Xkr8 as a complex with basigin (BSG) or neuroplastin (NPTN), type I membrane proteins in the Ig superfamily. In BSG −/− NPTN −/− cells, Xkr8 localized intracellularly, and the apoptosis stimuli failed to expose phosphatidylserine, indicating that BSG and NPTN chaperone Xkr8 to the plasma membrane to execute its scrambling activity. Mutational analyses of BSG showed that the atypical glutamic acid in the transmembrane region is required for BSG's association with Xkr8. In cells exposed to apoptotic signals, Xkr8 was cleaved at the C terminus and the Xkr8/BSG complex formed a higher-order complex, likely to be a heterotetramer consisting of two molecules of Xkr8 and two molecules of BSG or NPTN, suggesting that this cleavage causes the formation of a larger complex of Xkr8-BSG/NPTN for phospholipid scrambling.phospholipid scramblase | Xkr8 | chaperone | basigin | neuroplastin P hospholipids are asymmetrically distributed in plasma membranes by flippases that actively translocate phosphatidylserine (PtdSer) and phosphatidylethanolamine from the outer to inner leaflets of the membrane (1, 2). This asymmetrical distribution is disrupted in the activated platelets and apoptotic cells (3), in which the PtdSer exposed on the cell surface serves as a scaffold for blood clotting factors and as an "eat me" signal, respectively (4, 5). ATP11A and ATP11C, members of the P4-type ATPase family, act as flippases at the plasma membrane in most cells (6, 7). Two processes, flippase inactivation and scramblase activation, must occur to disrupt the asymmetrical phospholipid distribution and expose PtdSer on the cell surface (8).Scramblases are membrane proteins that nonspecifically and bidirectionally transport phospholipids between the two plasma membrane leaflets (9). Ca 2+ -activated phospholipid scrambling is mediated by membrane proteins that belong to the transmembrane protein (TMEM)16 (also called ANO) family (8). Of 10 human TMEM16-family members, 5 are Ca 2+ -activated phospholipid scramblases at plasma membranes. TMEM16F exposes PtdSer in activated platelets and osteoblasts (10-12). The tertiary structure of fungal TMEM16 and the biochemical characterization of mouse TMEM16 family members indicate that TMEM16 forms a homodimer that directly binds Ca 2+ (13).Phospholipid scrambling and PtdSer exposure in apoptotic cells is mediated by another family of membrane proteins, the XK-related (Xkr) proteins (8). Of 10 human Xkr family members, Xkr8 (ubiquitously expressed) and Xkr4 and Xkr9 (expressed in specific tissues) are cleaved by caspase during apoptosis to expose PtdSer (14, 15), but how the cleavage activates these Xkrs to scramble phospholipids is unknown. XK, the founding member of the Xkr family, associates with Kell, a type II membrane protein (16). Whether Xkr8 and other Xkr-family members associate with other proteins has not been addressed.In this report, we found that...

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“…6,11,12 At a second level, the surface exposure and release of a vast collection of cell danger-associated molecular patterns (CDAMPs) shape the response to stressed, dying and dead cells. Such CDAMPs include an ever-expanding list of 'findme' signals (also called chemotactic signals) that attract specific leukocyte populations, 13 'keep-out' signals (also called chemorepellents) that repel other leukocyte types, 'eatme' signals that stimulate phagocytosis in different ways, 14,15 'don't eat me' signals that avoid phagocytosis 15 and a collection of DAMPs that are often proteins or nucleic acids, which can only be fully released if the plasma membrane bursts, 6,11,12 as well as anti-inflammatory factors that mitigate local tissue reactions. 1,15 In a way, agonizing cells 'choose' by which phagocyte they will be engulfed, in which way their clearance will occur and what the consequences on the microenvironment will be.…”

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confidence: 99%

Dying cell recognition shapes the pathophysiology of cell death

Kroemer

2016

Cell Death Differ

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Exposure of phosphatidylserine on the cell surface

Cited by 386 publications

References 133 publications

Lipids and Ions Traverse the Membrane by the Same Physical Pathway in the nhTMEM16 Scramblase

Lipids and Ions Traverse the Membrane by the Same Physical Pathway in the nhTMEM16 Scramblase

Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure

Dying cell recognition shapes the pathophysiology of cell death

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