Purification and Partial Characterization of the Erythrocyte Kx Protein Deficient in McLeod Patients

Khamlichi, Samir; Bailly, Pascal; Blanchard, Dominique; Goossens, D.; Cartron, Jean‐Pierre; Bertrand, Olivier

doi:10.1111/j.1432-1033.1995.0931m.x

Cited by 44 publications

(34 citation statements)

References 19 publications

(10 reference statements)

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“…These results suggested that the active Xkr8 complex for the phospholipid scrambling is a tetramer consisting two caspasecleaved Xkr8 and two BSG or NPTN. Discussion XK, a member of the Xkr family, forms a complex with Kell, a type II membrane protein with metalloproteinase activity (25). XK connects to Kell via an S-S bond at the membrane-proximal regions (16).…”

Section: Effect Of Mouse Bsg and Nptn On Endogenous Xkr8-mediated Ptdsermentioning

confidence: 99%

Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure

Suzuki

Imanishi

Nagata

2016

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

114

132

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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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Section: Effect Of Mouse Bsg and Nptn On Endogenous Xkr8-mediated Ptdsermentioning

confidence: 99%

Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure

Suzuki

Imanishi

Nagata

2016

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

114

132

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“…1). 1,2 Kell, an endothelin-3-converting enzyme, is a 93-kDa type II membrane glycoprotein that belongs to the M13 family of zinc endopeptidases. 3,4 Like other members of the M13 family, Kell has an intracellular N-terminal domain and a large extracellular C-terminal domain which contains a zinc-binding catalytic pentapeptide consensus sequence, HExxH (in Kell, HELLH).…”

Section: The Kell and Xk Proteinsmentioning

confidence: 99%

Kell and Kx Blood Group Systems

Daniels

2013

Human Blood Groups

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Kell is a major human blood group system that is highly polymorphic, and at present it is known to express 28 different alloantigens. After the ABO and Rh systems, Kell is the most important blood group system in transfusion medicine, as some of the antigens are potent immunogens and their antibodies can cause severe transfusion reactions in mismatched blood transfusions and fetal anemia in feto-maternal incompatible pregnancies.The Kx blood group system is composed of a single antigen, Kx, which is carried on the XK protein. This system is important clinically because absence of XK protein, found in rare McLeod phenotypes, leads to red blood cell (RBC) acanthocytosis and to late onset abnormalities, usually commencing about midlife, involving the peripheral and central nervous systems, known as the McLeod syndrome.

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“…Biochemical studies in which Kell protein was isolated from red cells in nonreduced conditions, showed that Kell protein was associated with itself as an oligomer and was also complexed with other red cell membrane proteins (4). Later, immunoprecipitation of Kell protein in nonreduced conditions co-isolated XK, demonstrating that the two proteins exist as a disulfide-bonded complex on the red cell membrane (5). Further studies on the Kell-XK complex showed its absence in McLeod red cells and also demonstrated that although Ko (null) red cells have high Kx activity they contain less XK protein, indicating that lack of Kell protein may expose more Kx antigens on the cell surface (6).…”

mentioning

confidence: 99%

“…Positional cloning isolated the XK gene and predicted that it encodes a 444-amino acid protein that spans the red cell membrane 10 times and has structural characteristics of a membrane transporter (9). Since XK protein may only have one extracellular cysteine residue in the fifth extracellular loop, it was predicted that this residue may be involved in disulfide linkage with Kell protein, which has 15 extracellular cysteine residues and one cysteine in the transmembrane domain (5,10).…”

mentioning

confidence: 99%