Phospholipid Flippase Activity of the Reconstituted P-Glycoprotein Multidrug Transporter

Romsicki, Yolanda; Sharom, Frances J.

doi:10.1021/bi0024456

Cited by 141 publications

(164 citation statements)

References 64 publications

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“…This evidence is confirmed by reconstitution experiments, in which MsbA has been shown to translocate a wide variety of fluorescent-labeled phospholipids, albeit with low activity [72]. In the case of P-glycoprotein, studies in cell lines and reconstituted systems have suggested the involvement of this protein in transport of a variety of phospho-and glycolipids [65,70,[89][90][91]. However, this protein was first identified as the multidrug resistance transporter responsible for the inefficiency of long-term pharmacological treatments [92].…”

Section: Putative Catalytic Mechanism Of Abc Transporters Of the "Expmentioning

confidence: 80%

Structure and mechanism of ATP-dependent phospholipid transporters

López‐Marqués

Poulsen

Bailly

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background: ATP-binding cassette (ABC) transporters and P4-ATPases are two large and seemingly unrelated families of primary active pumps involved in moving phospholipids from one leaflet of a biological membrane to the other. Scope of review: This review aims to identify common mechanistic features in the way phospholipid flipping is carried out by two evolutionarily unrelated families of transporters. Major conclusions: Both protein families hydrolyze ATP, although they employ different mechanisms to use it, and have a comparable size with twelve transmembrane segments in the functional unit. Further, despite differences in overall architecture, both appear to operate by an alternating access mechanism and during transport they might allow access of phospholipids to the internal part of the transmembrane domain. The latter feature is obvious for ABC transporters, but phospholipids and other hydrophobic molecules have also been found embedded in P-type ATPase crystal structures. Taken together, in two diverse groups of pumps, nature appears to have evolved quite similar ways of flipping phospholipids. General significance: Our understanding of the structural basis for phospholipid flipping is still limited but it seems plausible that a general mechanism for phospholipid flipping exists in nature. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins.

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Section: Putative Catalytic Mechanism Of Abc Transporters Of the "Expmentioning

confidence: 80%

Structure and mechanism of ATP-dependent phospholipid transporters

López‐Marqués

Poulsen

Bailly

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

View full text Add to dashboard Cite

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“…The mechanism of fatty acid transport by these peroxisomal proteins has not been elucidated. Some evidence indicates that the human ABC protein P-glycoprotein acts as a flippase that transports phospholipids between leaflets of the plasma membrane (Romsicki and Sharom, 2001), although other mechanisms also have been suggested for protein P-glycoprotein and other ABC transporters (van Veen and Konings, 1997;van Veen, 2001).…”

Section: Discussionmentioning

confidence: 99%

The Arabidopsis pxa1 Mutant Is Defective in an ATP-Binding Cassette Transporter-Like Protein Required for Peroxisomal Fatty Acid β-Oxidation

2001

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Peroxisomes are important organelles in plant metabolism, containing all the enzymes required for fatty acid ␤-oxidation. More than 20 proteins are required for peroxisomal biogenesis and maintenance. The Arabidopsis pxa1 mutant, originally isolated because it is resistant to the auxin indole-3-butyric acid (IBA), developmentally arrests when germinated without supplemental sucrose, suggesting defects in fatty acid ␤-oxidation. Because IBA is converted to the more abundant auxin, indole-3-acetic acid (IAA), in a mechanism that parallels ␤-oxidation, the mutant is likely to be IBA resistant because it cannot convert IBA to IAA. Adult pxa1 plants grow slowly compared with wild type, with smaller rosettes, fewer leaves, and shorter inflorescence stems, indicating that PXA1 is important throughout development. We identified the molecular defect in pxa1 using a map-based positional approach. PXA1 encodes a predicted peroxisomal ATP-binding cassette transporter that is 42% identical to the human adrenoleukodystrophy (ALD) protein, which is defective in patients with the demyelinating disorder X-linked ALD. Homology to ALD protein and other human and yeast peroxisomal transporters suggests that PXA1 imports coenzyme A esters of fatty acids and IBA into the peroxisome for ␤-oxidation. The pxa1 mutant makes fewer lateral roots than wild type, both in response to IBA and without exogenous hormones, suggesting that the IAA derived from IBA during seedling development promotes lateral root formation.Peroxisomes are small, ubiquitous organelles encased in a single lipid bilayer that contain hydrogen peroxide-producing oxidases and catalases to inactivate reactive molecules (for review, see Gerhardt, 1992; Kindl, 1993; Olsen, 1998; Tabak et al., 1999). Arabidopsis and other oilseed plants ␤-oxidize longchain fatty acids (LCFAs) in peroxisomes to provide energy during germination. Plant peroxisomes also contain enzymes that act in photorespiration (Olsen, 1998) and the catabolism of branched-chain amino acids (Gerhardt, 1992; Zolman et al., 2001). In addition, seedlings and senescing tissues contain specialized peroxisomes called glyoxysomes that convert acetyl-coenzyme A (CoA) to succinate, which is transported to the mitochondria where it fuels the tricarboxylic acid cycle (Gerhardt, 1992; Olsen, 1998).Mammals metabolize fatty acids in both mitochondria and peroxisomes, and each organelle shortens a distinct subset of fatty acids (Lazarow, 1993; Tabak et al., 1999). In contrast, plants and yeast catabolize fatty acids exclusively in peroxisomes (Gerhardt, 1992; Kindl, 1993). Because peroxisomes lack DNA, proteins required for ␤-oxidation and other peroxisomal processes are translated in the cytoplasm and then imported (Olsen, 1998;Subramani, 1998; Tabak et al., 1999). Peroxisomal matrix proteins contain one of two peroxisomal targeting signals (PTSs). The PTS1 is made up of the amino acids "SKL" (or a conserved variant) at the extreme C termini of peroxisomal matrix-bound proteins (Gould et al., 1989). The PEX5 recept...

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“…In liposomes containing purified ABCB1 in an inverted orientation, an ATP-dependent transport activity was found when measuring the movement of fluorescent lipid analogues from outside to the inside of the liposomes. This lipid transport activity was inhibited by ABCB1 drug substrates; thus, drug and lipid transport activities are similar processes (Eckford & Sharom, 2005;Romsicki & Sharom, 2001). According to data in the literature, ABCB1 can also transport ceramides and sphingolipids (Clay & Sharom, 2013;Coleman et al, 2013;Radeva et al, 2005;Sharom, 2014), indicating a wide substrate specificity of ABCB1 also for lipid molecules.…”

Section: P0255mentioning

confidence: 91%