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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In situ architecture of the lipid transport protein VPS13C at ER–lysosome membrane contacts

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(29)

Published: July 13, 2022

VPS13 is a eukaryotic lipid transport protein localized at membrane contact sites. Previous studies suggested that it may transfer lipids between adjacent bilayers by bridge-like mechanism. Direct evidence for this hypothesis from full-length structure and electron microscopy (EM) in situ still missing, however. Here, we have capitalized on AlphaFold predictions to complement the structural information already available about generate model of human VPS13C, Parkinson's disease-linked paralog contacts endoplasmic reticulum (ER) endo/lysosomes. Such predicts an ∼30-nm rod with hydrophobic groove extends throughout its length. We further investigated whether such can be observed ER-endo/lysosome contacts. To aim, combined genetic approaches cryo-focused ion beam (cryo-FIB) milling cryo-electron tomography (cryo-ET) examine HeLa cells overexpressing (either full length or internal truncation) along VAP, anchoring binding partner ER. Using these methods, identified rod-like densities span space separating two membranes match predicted structures either VPS13C shorter truncated mutant, thus providing bridge transport.

Language: Английский

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A possible role for VPS13-family proteins in bulk lipid transfer, membrane expansion and organelle biogenesis

Journal of Cell Science, Journal Year: 2022, Volume and Issue: 135(5)

Published: March 1, 2022

At organelle-organelle contact sites, proteins have long been known to facilitate the rapid movement of lipids. Classically, this lipid transport involves extraction single lipids into a hydrophobic pocket on protein. Recently, new class transporter has described with physical characteristics that suggest these are likely function differently. They possess tracts can bind many at once and physically span entire gulf between membranes suggesting they may act as bridges bulk flow. Here, we review what learned regarding structure transporters, whose best characterized members VPS13 ATG2 proteins, their apparent coordination other lipid-mobilizing organelle membranes. We also discuss prevailing hypothesis in field, type membrane expansion through delivery lipids, well emerging hypotheses questions surrounding novel proteins.

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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Endoplasmic Reticulum Membrane Contact Sites, Lipid Transport, and Neurodegeneration

Cold Spring Harbor Perspectives in Biology, Journal Year: 2022, Volume and Issue: 15(4), P. a041257 - a041257

Published: Sept. 19, 2022

Andrés Guillén-Samander1,2 and Pietro De Camilli1,2 1Departments of Neuroscience Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration Repair, Yale University School Medicine, New Haven, Connecticut 06520, USA 2Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, Maryland 20815, Correspondence: pietro.decamilli{at}yale.edu

Language: Английский

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Structural basis of bulk lipid transfer by bridge-like lipid transfer protein LPD-3

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 22, 2024

Abstract Bridge-like lipid transport proteins (BLTPs) are an evolutionarily conserved family of that localize to membrane contact sites and thought mediate the bulk transfer lipids from a donor membrane, typically endoplasmic reticulum (ER), acceptor such as cell or organelle 1 . Despite fundamental importance BLTPs for cellular function, architecture, composition, mechanisms remain poorly characterized. Here, we present subunit composition cryo-electron microscopy structure native LPD-3 BLTP complex isolated transgenic C. elegans folds into elongated, rod-shaped tunnel whose interior is filled with ordered molecules coordinated by track ionizable residues line one side tunnel. forms two previously uncharacterized proteins, here named “Intake” “Spigot”, both which interact N-terminal end where enter Intake has three transmembrane helices, borders entrance tunnel; Spigot helix extends 80 Å along cytosolic surface LPD-3. Experiments in multiple model systems indicate plays role ER-PM site formation. Our structural data, together molecular dynamics simulations region bilayer, reveal protein-lipid interactions suggest how LPD-3-complex mediates provide foundation mechanistic studies BLTPs.

Language: Английский

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The bridge-like lipid transfer protein (BLTP) gene group: introducing new nomenclature based on structural homology indicating shared function

Human Genomics, Journal Year: 2022, Volume and Issue: 16(1)

Published: Dec. 2, 2022

The HUGO Gene Nomenclature Committee assigns unique symbols and names to human genes. use of approved nomenclature enables effective communication between researchers, there are multiple examples how the usage unapproved alias can lead confusion. We discuss here a recent update (May 2022) for set genes that encode proteins with shared repeating β-groove domain. Some encoded by in this group have already been shown function as lipid transporters. By working researchers field, we able introduce new root symbol (BLTP, which stands "bridge-like transfer protein") domain-based gene group. This not only reflects domain these proteins, but also takes into consideration mounting evidence transport function.

Language: Английский

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Biogenesis of Rab14-positive endosome buds at Golgi–endosome contacts by the RhoBTB3–SHIP164–Vps26B complex

Cell Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: April 2, 2024

Abstract Early endosomes (EEs) are crucial in cargo sorting within vesicular trafficking. While cargoes destined for degradation retained EEs and eventually transported to lysosomes, recycled the plasma membrane (PM) or Golgi undergo segregation into specialized structures known as EE buds during sorting. Despite this significance, molecular basis of expansion bud formation has been poorly understood. In study, we identify a protein complex comprising SHIP164, an ATPase RhoBTB3, retromer subunit Vps26B, which promotes at Golgi–EE contacts. Our findings reveal that Vps26B acts novel Rab14 effector, activity regulates association SHIP164 with EEs. Depletion leads enlarged + without buds, phenotype rescued by wild-type but not lipid transfer-defective mutants. Suppression RhoBTB3 mirrors effects depletion. Together, propose transport-dependent pathway mediated RhoBTB3–SHIP164–Vps26B contacts, is essential budding.

Language: Английский

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Emerging roles of ATG9/ATG9A in autophagy: implications for cell and neurobiology

Autophagy, Journal Year: 2024, Volume and Issue: 20(11), P. 2373 - 2387

Published: Aug. 4, 2024

Atg9, the only transmembrane protein among many autophagy-related proteins, was first identified in year 2000 yeast. Two homologs of ATG9A and ATG9B, have been found mammals. While ATG9B shows a tissue-specific expression pattern, such as placenta pituitary gland, is ubiquitously expressed. Additionally, deficiency leads to severe defects not at molecular cellular levels but also organismal level, suggesting key fundamental roles for ATG9A. The subcellular localization on small vesicles its functional relevance autophagy suggested potential role lipid supply during autophagosome biogenesis. Nevertheless, precise autophagic process has remained long-standing mystery, especially neurons. Recent findings, however, including structural, proteomic, biochemical analyses, provided new insights into function expansion phagophore membrane. In this review, we aim understand various aspects ATG9 (in invertebrates plants)/ATG9A mammals), localization, trafficking, other functions, nonneuronal cells neurons by comparing recent discoveries related ATG9/ATG9A proposing directions future research.

Language: Английский

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VPS13B is localized at the interface between Golgi cisternae and is a functional partner of FAM177A1

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(12)

Published: Sept. 27, 2024

Mutations in VPS13B, a member of protein family implicated bulk lipid transport between adjacent membranes, cause Cohen syndrome. VPS13B is known to be concentrated the Golgi complex, but its precise location within this organelle and thus site(s) where it achieves remains unclear. Here, we show that localized at interface proximal distal subcompartments complex reformation after Brefeldin A (BFA)–induced disruption delayed KO cells. This delay phenocopied by loss FAM177A1, unknown function reported interactor whose mutations also result developmental disorder. In zebrafish, vps13b ortholog, not previously annotated organism, genetically interacts with fam177a1. Collectively, these findings raise possibility may play role dynamics membranes assisted FAM177A1.

Language: Английский

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