Substrate trajectory through phospholipid-transporting P4-ATPases

Williamson, Patrick

doi:10.1042/bst20140137

Cited by 5 publications

(4 citation statements)

References 36 publications

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“…Like other P-type ATPases, P4-ATPases contain a large catalytic or α-subunit composed of a nucleotide binding domain (N-domain), a phosphorylation domain (P-domain), and an actuator domain (A-domain) which are involved in the ATP reaction cycle, and a membrane domain (M-domain) consisting of 10 predicted transmembrane segments which serve as the pathway for the translocation of phospholipids across cell membranes 1 , 17 – 21 . In addition, some mammalian P4-ATPases contain an extended C-terminal segment implicated in protein folding and regulation of its activity 22 .…”

Section: Introductionmentioning

confidence: 99%

Proteomic Analysis and Functional Characterization of P4-ATPase Phospholipid Flippases from Murine Tissues

Wang

Molday

Hii

et al. 2018

Sci Rep

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P4-ATPases are a subfamily of P-type ATPases that flip phospholipids across membranes to generate lipid asymmetry, a property vital to many cellular processes. Mutations in several P4-ATPases have been linked to severe neurodegenerative and metabolic disorders. Most P4-ATPases associate with one of three accessory subunit isoforms known as CDC50A (TMEM30A), CDC50B (TMEM30B), and CDC50C (TMEM30C). To identify P4-ATPases that associate with CDC50A, in vivo, and determine their tissue distribution, we isolated P4-ATPases-CDC50A complexes from retina, brain, liver, testes, and kidney on a CDC50A immunoaffinity column and identified and quantified P4-ATPases from their tryptic peptides by mass spectrometry. Of the 12 P4-ATPase that associate with CDC50 subunits, 10 P4-ATPases were detected. Four P4-ATPases (ATP8A1, ATP11A, ATP11B, ATP11C) were present in all five tissues. ATP10D was found in low amounts in liver, brain, testes, and kidney, and ATP8A2 was present in significant amounts in retina, brain, and testes. ATP8B1 was detected only in liver, ATP8B3 and ATP10A only in testes, and ATP8B2 primarily in brain. We also show that ATP11A, ATP11B and ATP11C, like ATP8A1 and ATP8A2, selectively flip phosphatidylserine and phosphatidylethanolamine across membranes. These studies provide new insight into the tissue distribution, relative abundance, subunit interactions and substrate specificity of P4-ATPase-CDC50A complexes.

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Section: Introductionmentioning

confidence: 99%

Proteomic Analysis and Functional Characterization of P4-ATPase Phospholipid Flippases from Murine Tissues

Wang

Molday

Hii

et al. 2018

Sci Rep

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“…Another puzzling feature of this model is that TM5 is situated behind TM4 and is clearly separated from the water-filled cavities, since previously obtained experimental evidence for ATP8A2 demonstrated that a specific conserved lysine residue in TM5 is essential for phospholipid translocation 7 . An alternative theoretical model has been recently proposed based on the plasma membrane H + -ATPase structure 11 . This theoretical model suggests that a water-filled cavity exists in P4 ATPases that is analogous to the one in the crystal structure of H + -ATPases, between TM4, TM5, and TM6.…”

Section: Introductionmentioning

confidence: 99%

Phospholipid flipping involves a central cavity in P4 ATPases

Jensen

Costa

Duelli

et al. 2017

Sci Rep

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P4 ATPase flippases translocate phospholipids across biomembranes, thus contributing to the establishment of transmembrane lipid asymmetry, a feature important for multiple cellular processes. The mechanism by which such phospholipid flipping occurs remains elusive as P4 ATPases transport a giant substrate very different from that of other P-type ATPases such as Na+/K+- and Ca2+-ATPases. Based on available crystal structures of cation-transporting P-type ATPases, we generated a structural model of the broad-specificity flippase ALA10. In this model, a cavity delimited by transmembrane segments TM3, TM4, and TM5 is present in the transmembrane domain at a similar position as the cation-binding region in related P-type ATPases. Docking of a phosphatidylcholine headgroup in silico showed that the cavity can accommodate a phospholipid headgroup, likely leaving the fatty acid tails in contact with the hydrophobic portion of the lipid bilayer. Mutagenesis data support this interpretation and suggests that two residues in TM4 (Y374 and F375) are important for coordination of the phospholipid headgroup. Our results point to a general mechanism of lipid translocation by P4 ATPases, which closely resembles that of cation-transporting pumps, through coordination of the hydrophilic portion of the substrate in a central membrane cavity.

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“…As recently outlined [47], the phospholipid substrate trajectory through P4-ATPases is yet poorly understood and under careful investigation. On the basis of the present study, a plausible hypothesis is that the CDC50 proteins are located near the transport pathway and participate in the transport mechanism.…”

Section: Discussionmentioning

confidence: 99%

Specific mutations in mammalian P4‐ATPase ATP8A2 catalytic subunit entail differential glycosylation of the accessory CDC50A subunit

et al. 2015

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a b s t r a c t P4-ATPases, or flippases, translocate phospholipids between the two leaflets of eukaryotic biological membranes. They are essential to the physiologically crucial phospholipid asymmetry and involved in severe diseases, but their molecular structure and mechanism are still unresolved. Here, we show that in an extensive mutational alanine screening of the mammalian flippase ATP8A2 catalytic subunit, five mutations stand out by leading to reduced glycosylation of the accessory subunit CDC50A. These mutations may disturb the interaction between the subunits.

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Substrate trajectory through phospholipid-transporting P4-ATPases

Cited by 5 publications

References 36 publications

Proteomic Analysis and Functional Characterization of P4-ATPase Phospholipid Flippases from Murine Tissues

Proteomic Analysis and Functional Characterization of P4-ATPase Phospholipid Flippases from Murine Tissues

Phospholipid flipping involves a central cavity in P4 ATPases

Specific mutations in mammalian P4‐ATPase ATP8A2 catalytic subunit entail differential glycosylation of the accessory CDC50A subunit

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