Molecular architecture of human LYCHOS involved in lysosomal cholesterol signaling

Nature Structural & Molecular Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Language: Английский

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The role of indole‐3‐acetic acid and characterization of PIN transporters in complex streptophyte alga Chara braunii

New Phytologist, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

Auxin, indole-3-acetic acid (IAA), is a key phytohormone with diverse morphogenic roles in land plants, but its function and transport mechanisms algae remain poorly understood. We therefore aimed to explore the role of IAA complex, streptophyte Chara braunii. Here, we described novel responses C. braunii characterized two homologs PIN auxin efflux carriers: CbPINa CbPINc. determined their localization using epitope-specific antibodies tested heterologous plant models. Further, phosphoproteomic analysis, identified IAA-induced phosphorylation events. The thallus regeneration assay showed that promotes elongation side branch development. Immunolocalization CbPINc confirmed presence on plasma membrane vegetative generative cells However, functional assays tobacco BY-2 demonstrated affects transport, whereas does not. effective acceleration cytoplasmic streaming evolutionary conserved targets such as homolog RAF-like kinase. These findings suggest that, although canonical PIN-mediated might not be fully Chara, involved morphogenesis fast signaling processes.

Language: Английский

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Illuminating cholesterol-mTORC1 signaling: LYCHOS in focus

Structure, Journal Year: 2025, Volume and Issue: 33(2), P. 218 - 220

Published: Feb. 1, 2025

Language: Английский

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Mechanisms and functions of lysosomal lipid homeostasis

Cell chemical biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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Multiple Pendants-Bearing Triglucosides for Membrane Protein Studies: Effects of Pendant Length and Number on Micelle Interior Hydration and Protein Stability

Biomacromolecules, Journal Year: 2025, Volume and Issue: unknown

Published: March 14, 2025

Membrane proteins play central roles in cell physiology and are the targets of over 50% FDA-approved drugs. In present study, we prepared single alkyl-chained triglucosides decorated with multiple pendants, designated pendant-bearing glucosides (MPGs), to enhance membrane protein stability. The new detergents feature two four pendants varying size at hydrophilic–lipophilic interfaces, MPG-Ds MPG-Ts, respectively. When tested model proteins, including human adrenergic receptor (β2AR), tetra-pendant-bearing MPGs (MPG-Ts) demonstrated superior performance compared dipendant analogs (MPG-Ds) gold standard DDM. All-atom molecular dynamics (MD) simulations results reveal that four-pendant configuration this detergent is remarkably effective excluding water from hydrophobic micelle interiors DDM, an unprecedented detergent. Our findings provide a novel strategy for designing water-resistant detergents, advancing field research.

Language: Английский

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Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 21, 2025

The lysosome serves as an essential nutrient-sensing hub within the cell, where mechanistic target of rapamycin complex 1 (mTORC1) is activated. Lysosomal cholesterol signaling (LYCHOS), a membrane protein, has been identified sensor that couples concentration to mTORC1 activation. However, molecular basis unknown. Here, we determine cryo-electron microscopy (cryo-EM) structure human LYCHOS at resolution 3.1 Å, revealing cholesterol-like density interface between permease and G-protein coupled receptor (GPCR) domains. Advanced 3D classification reveals two distinct states LYCHOS. Comparative structural analysis these demonstrated cholesterol-related movement GPCR domain relative domain, providing insights into how senses lysosomal levels. Additionally, identify indoxyl sulfate (IS) binding ligand confirmed by LYCHOS-IS structure. Overall, our study provides foundation indicates additional directions for further investigation role in pathway. LYCHOS, coordinates with authors report its cryo-EM structures, site, demonstrate ability bind gut-derived uremic toxin, indole sulfate.

Language: Английский

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G protein-coupled receptor diversity and evolution in the closest living relatives of Metazoa

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

ABSTRACT G protein-coupled receptors (GPCRs) play a pivotal role in the perception of environmental cues across eukaryotic diversity. Although GPCRs have been relatively well characterized metazoans, GPCR signaling is poorly understood their sister group, choanoflagellates, and other close relatives metazoans (CRMs). Here, we examine diversity evolution choanoflagellates by curating catalog 918 GPCRs, 141 proteins, 367 associated regulators from 23 choanoflagellate genomes transcriptomes. We found that repertoire larger more diverse than previously anticipated, with 18 families which 12 are newly identified these organisms. Comparative analyses revealed most conserved and/or lineages. Adhesion TKL/Ks abundant choanoflagellates. Importantly, identification repertoires CRMs non-metazoans refines our understanding metazoan reveals existence unreported at root tree.

Language: Английский

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Cholesterol finds its pocket in LYCHOS

Nature Structural & Molecular Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 28, 2025

Language: Английский

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Lysosomal Ion Channels and Transporters: Recent Findings, Therapeutic Potential, and Technical Approaches

Bioelectricity, Journal Year: 2025, Volume and Issue: 7(1), P. 29 - 57

Published: March 1, 2025

In recent years, there has been a growing interest in lysosomal ion channels and transporters due to their critical role maintaining function involvement variety of diseases, particularly storage cancer, neurodegenerative disorders. Recent advancements research techniques, including manual automated patch clamp (APC) electrophysiology, solid-supported membrane-based electrophysiology (SSME), fluorescence-based imaging, have further enhanced our ability investigate both physiological pathological conditions, spurring drug discovery efforts. Several pharmaceutical companies are now developing therapies aimed at modulating these improve disease. Small molecules targeting like transient receptor potential mucolipin (TRPML) 1 TMEM175, as well drugs pH, currently preclinical clinical development. This review provides an overview the health disease, highlights cutting-edge techniques used study them, discusses therapeutic treatment various diseases. Furthermore, addition summarizing discoveries, we contribute novel functional data on cystinosin, TRPML1, two-pore channel 2 (TPC2), utilizing SSME APC approaches.

Language: Английский

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Over 25 years of decrypting PIN-mediated plant development

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 15, 2024

Abstract Identification of PIN exporters for auxin, the major coordinative signal in plants, some 25 years ago, signifies a landmark our understanding plant-specific mechanisms underlying development and adaptation. Auxin is directionally transported throughout plant body; unique feature already envisioned by Darwin solidified PINs’ discovery characterization. The PIN-based auxin distribution network with its complex regulations expression, localization activity turned out to underlie remarkable multitude developmental processes represents means integrate endogenous environmental signals. Given recent anniversary, we here summarize past current developments this exciting field.

Language: Английский

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