Structures of a P4-ATPase lipid flippase in lipid bilayers

He, Yilin; Xu, Jinkun; Wu, Xiaofei; Li, Long

doi:10.1101/2020.03.14.992305

Cited by 4 publications

(12 citation statements)

References 48 publications

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“…Local membrane thinning has been observed with proteins that are involved in lipid movement across the bilayer. For example, in one nucleotide state of a P4 type ATPase, the lipid bilayer is locally thinned to about half the normal membrane thickness [69]. The distortion of the lipid bilayer, together with specific binding sites whose affinity changes during the ATPase cycle, likely facilitates the flipping of certain phospholipids.…”

Section: Membrane Thinning Can Serve Purposes Other Than Protein Translocationmentioning

confidence: 99%

Translocation of Proteins through a Distorted Lipid Bilayer

Rapoport

2021

Trends in Cell Biology

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Section: Membrane Thinning Can Serve Purposes Other Than Protein Translocationmentioning

confidence: 99%

Translocation of Proteins through a Distorted Lipid Bilayer

Rapoport

2021

Trends in Cell Biology

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“…The first structural insights into P4 flippase function were recently provided by the cryogenic electron microscopy (cryo-EM) structure of a key functional E2P state of the yeast Drs2p P4-ATPase ( Timcenko et al, 2019 ). Similar structures of Drs2p and structures of other flippases, including mammalian ATP8A1, ATP11C and yeast Neo1p, Dnf1p and Dnf2p have been also subsequently determined ( Bai et al, 2019; Hiraizumi et al, 2019; Nakanishi et al, 2020a,b; He et al, 2020; Bai et al, 2020, 2021; Timcenko et al, 2021 ). Drs2p is found in the trans-Golgi network membrane, where it acts as a PS lipid flippase, but has also been shown to transport PE to a lesser extent ( Natarajan et al, 2004; Azouaoui et al, 2014 ).…”

Section: Introductionmentioning

confidence: 83%

“…(B) The average density map of the phosphate head group obtained from coarse-grained simulations with the CG5 model (magenta mesh) is superposed with the location of PL phosphates in the experimentally determined flippases (coloured spheres). These structures include the E2Pi state of ATP8A1 (PDB 6K7M(Hiraizumi et al, 2019), blue), the E2P state of ATP11C (PDB 6LKN(Nakanishi et al, 2020), yellow), and the E2P and E1-ATP states of Dnf1 (PDB 6LCP and 6LCR(He et al, 2020), green and red).…”

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confidence: 99%

Substrate Transport and Specificity in a Phospholipid Flippase

Wang

Lyons

Timcenko

et al. 2020

Preprint

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Type-IV P-type ATPases are lipid flippases which help maintain asymmetric 14 phospholipid distribution in eukaryotic membranes by using ATP hydrolysis to drive unidirectional 15 translocation of phospholipid substrates. Recent Cryo-EM and crystal structures have provided a 16 detailed view of flippases, and we here use molecular dynamics simulations of the yeast flippase 17Drs2p:Cdc50p in an outward open conformation to study the first steps of phospholipid transport. 18 Our simulations show phospholipid binding to a groove and subsequent movement towards the 19 centre of the membrane, and reveal a preference for phosphatidylserine lipids. We find that the 20 lipid head group stays solvated in the groove while the lipid tails stay in the membrane during the 21 (half) transport event. The flippase also induces deformation and thinning of the outer leaflet. 22 Together, our simulations provide insight into substrate binding to lipid flippases and suggest that 23 multiple sites and steps in the functional cycle contribute to substrate selectivity. 24 25 30 et al., 2020), so that phosphatidylserine (PS) and phosphatidylethanolamine (PE) are enriched in 31 the inner (cytosolic) leaflet, while phosphatidylcholine (PC) and sphingomyelin are found more 32 often in the outer (exoplasmic) leaflet. The maintenance or modulation of the asymmetric PL 33 distribution can play a central role in the proper functioning of the cell; for example, an increase in 34 the population of PS in the outer leaflet of the plasma membrane serves as an 'eat-me' signal to 35 induce phagocytosis (Fadok et al., 1992), whereas a decrease of the population of the negatively 36 charged PS on the inner leaflet may result in a release of proteins with positively charged residues 37 from the membrane to the cytosol by an 'electrostatic switch' mechanism (Lipp et al., 2019). 38 It is kinetically unfavourable for PLs to 'flip' (move from the outside to inside) and 'flop' (inside to 39 outside), and it requires energy to maintain asymmetric lipid distributions. Therefore, cells contain 40 1 of 16 Manuscript to be submitted a number of different PL transporters that fall into three broad categories: scramblases, floppases, 41 and flippases (Montigny et al., 2016). Scramblases (such as TMEM16 (Falzone et al., 2018) and a 42 number of G-protein coupled receptors (Menon et al., 2011)) facilitate the movement of PLs in both 43 directions without energy consumption. In contrast, flippases and floppases are unidirectional and 44 ATP-dependent. They use the energy from ATP hydrolysis to flip or flop specific PLs against their 45 concentration gradient. Indeed, PL flip/flop in the presence of ATP-dependent flippases/floppases 46 typically occurs at the time scale of ∼10-100 ms, much faster than that of the spontaneous process 47 which is typically several hours or longer (Kobayashi and Menon, 2018). 48 The majority of lipid flippases constitute the type IV (P4) subgroup of the P-type ATPase super-49 family that includes the well-characterized + / + -ATPas...

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“…[38]. Recent cryo-EM studies have provided a structural glimpse on the overall archi-tecture of P4-ATPases [38][39][40][41].…”

Section: P4-atpase Phospholipid Transportersmentioning

confidence: 99%

Transporters Beam Signals from Cell Membranes

Ristovski¹,

Farhat²,

Bancud³

et al. 2021

Preprint

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Lipid composition in the cellular membranes plays an important role in maintaining the struc-tural integrity of cells and in regulating cellular signaling that controls functions of both mem-brane-anchored and cytoplasmic proteins. ATP-dependent ABC and P4-ATPase lipid transport-ers, two integral membrane proteins, are known to contribute to lipid translocation across the li-pid bilayers on the cellular membranes. In this review, we will highlight current knowledge about the role of cholesterol and phospholipids of cellular membrane in regulating cell signaling and how lipid transporters participate this process.

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Structures of a P4-ATPase lipid flippase in lipid bilayers

Cited by 4 publications

References 48 publications

Translocation of Proteins through a Distorted Lipid Bilayer

Translocation of Proteins through a Distorted Lipid Bilayer

Substrate Transport and Specificity in a Phospholipid Flippase

Transporters Beam Signals from Cell Membranes

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