Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(8), P. 576 - 596

Published: April 27, 2023

Language: Английский

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RBG Motif Bridge-Like Lipid Transport Proteins: Structure, Functions, and Open Questions

Annual Review of Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 39(1), P. 409 - 434

Published: July 5, 2023

The life of eukaryotic cells requires the transport lipids between membranes, which are separated by aqueous environment cytosol. Vesicle-mediated traffic along secretory and endocytic pathways lipid transfer proteins (LTPs) cooperate in this transport. Until recently, known LTPs were shown to carry one or a few at time thought mediate shuttle-like mechanisms. Over last years, new family has been discovered that is defined repeating β-groove (RBG) rod-like structure with hydrophobic channel running their entire length. This localization these membrane contact sites suggest bridge-like mechanism Mutations some result neurodegenerative developmental disorders. Here we review properties well-established putative physiological roles proteins, highlight many questions remain open about functions.

Language: Английский

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Insights from lipidomics into the terminal maturation of circulating human reticulocytes

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 27, 2025

Abstract In the age of “omics”, lipidomics erythropoiesis is still missing. How reticulocytes mature in circulation into functional erythrocytes also largely unknown. We have isolated here two populations human circulating at different levels maturation, and three subpopulations age, characterized evolution their lipidome. (Sphingomyelin+cholesterol) partly phosphatidylethanolamine increase relative to total lipids, whereas phosphatidylcholine phosphatidylserine decrease from immature erythrocytes, same time as surface area per cell decreases. The amounts more than 70 phospholipid subclasses, based on number carbon atoms (12–24) double bonds (0–6) fatty acids linked phospholipid, change process. As cannot perform de-novo synthesis, lipid remodeling likely requires selective removal phospholipids membrane or exchange with plasma both, possible involvement transfer proteins such VPS13A, which expressed erythrocytes. These findings not only shed light fundamental aspects red blood physiology but raise intriguing questions surrounding protein-lipid interactions, architecture, trafficking mechanisms.

Language: Английский

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A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(35)

Published: Aug. 22, 2022

Chorea-acanthocytosis (ChAc) and McLeod syndrome are diseases with shared clinical manifestations caused by mutations in VPS13A XK, respectively. Key features of these conditions the degeneration caudate neurons presence abnormally shaped erythrocytes. XK belongs to a family plasma membrane (PM) lipid scramblases whose action results exposure PtdSer at cell surface. is an endoplasmic reticulum (ER)-anchored transfer protein putative role transport lipids contacts ER other membranes. Recently were reported interact still unknown mechanisms. So far, however, there no evidence for colocalization two proteins PM, where resides, as was shown be localized between either mitochondria or droplets. Here we show that can also localize ER–PM via binding its PH domain cytosolic loop such interaction regulated intramolecular within both highly expressed neurons. Binding competitive intracellular membranes mediate tethering functions VPS13A. Our findings support model according which VPS13A-dependent PM coupled scrambling PM. They raise possibility defective surface may responsible neurodegeneration.

Language: Английский

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Parallel phospholipid transfer by Vps13 and Atg2 determines autophagosome biogenesis dynamics

The Journal of Cell Biology, Journal Year: 2023, Volume and Issue: 222(7)

Published: April 28, 2023

During autophagy, rapid membrane assembly expands small phagophores into large double-membrane autophagosomes. Theoretical modeling predicts that the majority of autophagosomal phospholipids are derived from highly efficient non-vesicular phospholipid transfer (PLT) across phagophore-ER contacts (PERCS). Currently, tether Atg2 is only PLT protein known to drive phagophore expansion in vivo. Here, our quantitative live-cell imaging analysis reveals a poor correlation between duration and size forming autophagosomes number molecules at PERCS starving yeast cells. Strikingly, we find Atg2-mediated non-rate limiting for autophagosome biogenesis because Vps13 localizes rim promotes parallel with Atg2. In absence Vps13, determines an apparent vivo rate ∼200 per molecule second. We propose conserved proteins cooperate channeling organelle contact sites non-rate-limiting during biogenesis.

Language: Английский

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Phosphatidylserine transport in cell life and death

Current Opinion in Cell Biology, Journal Year: 2023, Volume and Issue: 83, P. 102192 - 102192

Published: July 4, 2023

Language: Английский

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Exploring the ATG9A interactome uncovers interaction with VPS13A

Journal of Cell Science, Journal Year: 2024, Volume and Issue: 137(4)

Published: Jan. 31, 2024

ATG9A, a transmembrane protein of the core autophagy pathway, cycles between Golgi, endosomes and vesicular compartment. ATG9A was recently shown to act as lipid scramblase, this function is thought require its interaction with another protein, ATG2A, which acts transfer protein. Together, ATG2A are proposed expand growing autophagosome. However, implicated in other pathways including membrane repair droplet homeostasis. To elucidate interactors within or beyond autophagy, we performed an interactome analysis through mass spectrometry. This revealed host proteins involved synthesis trafficking, ACSL3, VPS13A VPS13C. Furthermore, show that directly interacts forms complex distinct from ATG9A-ATG2A complex.

Language: Английский

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Sequence Analysis and Structural Predictions of Lipid Transfer Bridges in the Repeating Beta Groove (RBG) Superfamily Reveal Past and Present Domain Variations Affecting Form, Function and Interactions of VPS13, ATG2, SHIP164, Hobbit and Tweek

Contact, Journal Year: 2022, Volume and Issue: 5, P. 251525642211343 - 251525642211343

Published: Jan. 1, 2022

Lipid transfer between organelles requires proteins that shield the hydrophobic portions of lipids as they cross cytoplasm. In last decade a new structural form lipid protein (LTP) has been found: long grooves made beta-sheet bridge at membrane contact sites. Eukaryotes have five families bridge-like LTPs: VPS13, ATG2, SHIP164, Hobbit and Tweek. These are unified into single superfamily through their bridges being composed just one domain, called repeating beta groove (RBG) which builds rod shaped multimers with hydrophobic-lined hydrophilic exterior. Here, sequences predicted structures RBG were analyzed in depth. Phylogenetics showed eukaryotic common ancestor contained all proteins, duplicated VPS13s. The current set appears to arisen even earlier ancestors from shorter forms 4 domains. extreme ends most amphipathic helices might be an adaptation for direct or indirect bilayer interaction, although this yet tested. exception is C-terminus instead coiled-coil. Finally, exterior surfaces shown conserved residues along length, indicating sites partner interactions almost unknown. findings can inform future cell biological biochemical experiments.

Language: Английский

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Interaction between VPS13A and the XK scramblase is important for VPS13A function in humans

Journal of Cell Science, Journal Year: 2022, Volume and Issue: 135(17)

Published: Aug. 11, 2022

VPS13 family proteins form conduits between the membranes of different organelles through which lipids are transferred. In humans, there four paralogs, and mutations in genes encoding each them associated with inherited disorders. contain multiple conserved domains. The Vps13 adaptor-binding (VAB) domain binds to adaptor that recruit specific membrane contact sites. This work demonstrates importance a VPS13A function. pleckstrin homology (PH) at C-terminal region is required complex XK scramblase for co-localization within cell. Alphafold modeling was used predict an interaction surface XK. Mutations this disrupt both formation two proteins. Mutant alleles found patients disease truncate PH domain. phenotypic similarities McLeod syndrome caused by XK, respectively, argue loss VPS13A-XK basis diseases.

Language: Английский

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Neuroacanthocytosis Syndromes: The Clinical Perspective

Contact, Journal Year: 2023, Volume and Issue: 6

Published: Jan. 1, 2023

The two very rare neurodegenerative diseases historically known as the “neuroacanthocytosis syndromes” are due to mutations of either VPS13A or XK. These phenotypically similar disorders that affect primarily basal ganglia and hence result in involuntary abnormal movements well neuropsychiatric cognitive alterations. There other shared features such abnormalities red cell membranes which acanthocytes, whose relationship neurodegeneration is not yet known. Recent insights into functions these proteins suggest dysfunction lipid processing trafficking at subcellular level may provide a mechanism for neuronal death, potentially target therapeutic interventions.

Language: Английский

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