Phospholipid flippase ATP11C is endocytosed and downregulated following Ca2+-mediated protein kinase C activation

Takatsu, Hiroyuki; Takayama, Masahiro; Naito, Takashi; Takada, Naoto; Tsumagari, Kazuya; Ishihama, Yasushi; Nakayama, Kazuhisa; Shin, Hye‐Won

doi:10.1038/s41467-017-01338-1

Cited by 50 publications

(71 citation statements)

References 84 publications

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“…S6). In the ATP8A1 E2P state, a membrane crevice is not formed at all 31 , probably due to its longer C-terminal regulatory domain compared with that in ATP11C (∼38 amino acids) 38 (Fig. S4).…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of a human plasma membrane phospholipid flippase

Nakanishi¹,

Irie

Segawa

et al. 2019

Preprint

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1 5 ATP11C, a member of P4-ATPase flippase, exclusively translocates phosphatidylserine 1 6 from the outer to the inner leaflets of the plasma membrane, and maintains the 1 7 asymmetric distribution of phosphatidylserine in the living cell. However, the 1 8 mechanisms by which ATP11C translocates phosphatidylserine remain elusive. Here we 1 9 show the crystal structures of a human plasma membrane flippase, ATP11C-CDC50A 2 0 complex, in an outward-open E2P conformation. Two phosphatidylserine molecules are 2 1 in a conduit that continues from the cell surface to the occlusion site in the middle of the 2 2 membrane. Mutations in either of the phosphotidylserine binding sites or along the 2 3pathway between significantly impairs specific ATPase and transport activities. We 2 4 propose a model for phosphatidylserine translocation from the outer to the inner leaflet 2 5 of the plasma membrane. 2 6 2 7 3

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Section: Resultsmentioning

confidence: 99%

Crystal structure of a human plasma membrane phospholipid flippase

Nakanishi¹,

Irie

Segawa

et al. 2019

Preprint

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“…exposure requires inhibition of PS flippases and activation of a scramblase in apoptotic cells (10,23). In living cells, the PS flippase ATP11C is endocytosed and down-regulated via Ca 2+ signaling and returns to the plasma membrane soon after this signaling is switched off (53). Various mechanisms therefore regulate the activities of PS flippases at the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the ATPase activities of affinity-purified ATP8A1 and ATP8A2 are enhanced in the presence of their substrates (PS and PE) in vitro (22,69). ATP11A and ATP11C transport NBD-PS and NBD-PE at the plasma membrane in many cell types, including HeLa cells, CHO-K1 cells, and leukocytes (25,50,53,70,71). ATP11A, ATP11B, and ATP11C translocate NBD-PS in reconstituted liposomes, and the addition of PS and PE enhances the ATPase activities of these affinity-purified ATPases in vitro (26,50).…”

Section: Lipid Transport By P4-atpasesmentioning

confidence: 99%

“…P4-ATPases most likely regulate transbilayer lipid dynamics for specialized cellular processes, such as membrane trafficking and cell migration, by functioning where they predominantly localize (9,22,29,51,52). Although it remains unknown how P4-ATPases localize to specific organelles, at least the Nterminal cytoplasmic region of ATP9B is critical for its localization to the Golgi complex (46) and the C-terminal cytoplasmic region of ATP11C is responsible for Ca 2+ signaling-dependent endocytosis (53).…”

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confidence: 99%

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Substrates of P4‐ATPases: beyond aminophospholipids (phosphatidylserine and phosphatidylethanolamine)

Shin

Takatsu

2018

FASEB j.

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P4‐ATPases, a subfamily of P‐type ATPases, were initially identified as aminophospholipid translocases in eukaryotic membranes. These proteins generate and maintain membrane lipid asymmetry by translocating aminophospholipids (phosphatidylserine and phosphatidylethanolamine) from the exoplasmic/lumenal leaflet to the cytoplasmic leaflet. The human genome encodes 14 P4‐ATPases, and the cellular localizations, substrate specificities, and cellular roles of these proteins were recently revealed. Numerous P4‐ATPases, including ATP8A1, ATP8A2, ATP11A, ATP11B, and ATP11C, transport phosphatidylserine. By contrast, ATP8B1, ATP8B2, and ATP10A transport phosphatidylcholine but not aminophospholipids, although there is a discrepancy regarding the substrate of ATP8B1 in the literature. Some yeast and plant P4‐ATPases can also translocate phosphatidylcholine. At least 2 P4‐ATPases (ATP8A2 and ATP8B1) are associated with severe human diseases, and other P4‐ATPases are implicated in various pathophysiologic conditions in mouse models. Here, we discuss the cellular functions of phosphatidylcholine flippases and suggest a model for the phenotype of progressive familial intrahepatic cholestasis 1 caused by a defect in ATP8B1.—Shin, H.‐W., Takatsu, H. Substrates of P4‐ATPases: beyond aminophospholipids (phosphatidylserine and phosphatidylethanolamine). FASEB J. 33, 3087–3096 (2019). http://www.fasebj.org

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“…Mounting evidence reveals that the asymmetrically distributed phospholipids are maintained by P4-ATPases (also called flippases), which translocate phospholipids from the exoplasmic leaflet to the cytoplasmic leaflet [1,[5][6][7][8]20]. In mammals, 14 members of P4-ATPases, designated ATP8A1 through ATP11C， have been identified [21]. ATP8A1, ATP8A2, ATP8B1, ATP8B2, ATP8B4, ATP10A, ATP10D, ATP11A, and ATP11C are localized to the plasma membrane, whereas ATP9A, ATP9B, ATP10B, and ATP11B are localized to intracellular membranes [1,6,9,18,22,23].…”

Section: Introductionmentioning

confidence: 99%

Disease mutation study identifies essential residues for phosphatidylserine flippase ATP11A

Sun

Tian

Liu

et al. 2020

Preprint

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PS flippase (P4-ATPase) transports PS from the outer to the inner leaflet of the lipid bilayer in the membrane to maintain PS asymmetry, which is important for biological activity of the cell. ATP11A is expressed in multiple tissues and plays a role in myotube formation. However, detailed cellular function of ATP11A remains elusive. Mutation analysis revealed that I91, L308 and E897 residues in ATP8A2 are important for flippase activity. In order to investigate the roles of these corresponding amino acid residues in ATP11A, we assessed the expression and flippase activity of the respective ATP11A mutant proteins. ATP11A mainly localizes to the Golgi when co-expressed with TMEM30A, the β-subunit of the complex. Y300F and D913K mutations affect correct Golgi localization and PS stimulated flippase activity. In addition, Y300F mutation causes reduced ATP11A expression. Our data provides insight into essential residues for expression and flippase activity of ATP11A.

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Phospholipid flippase ATP11C is endocytosed and downregulated following Ca2+-mediated protein kinase C activation

Cited by 50 publications

References 84 publications

Crystal structure of a human plasma membrane phospholipid flippase

Crystal structure of a human plasma membrane phospholipid flippase

Substrates of P4‐ATPases: beyond aminophospholipids (phosphatidylserine and phosphatidylethanolamine)

Disease mutation study identifies essential residues for phosphatidylserine flippase ATP11A

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