Structural insights into the mechanism of phosphate recognition and transport by XPR1

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 2, 2025

XPR1 is the sole protein known to transport inorganic phosphate (Pi) out of cells, a function conserved across species from yeast mammals. Human variants lead cerebral calcium-phosphate deposition and primary familial brain calcification (PFBC), hereditary neurodegenerative disorder. Here, we present cryo-EM structure human in both its Pi-unbound various Pi-bound states. features 10 transmembrane α-helices forming an ion channel-like structure, with multiple Pi recognition sites along channel. Pathogenic mutations two arginine residues, which line translocation channel, disrupt transport. Molecular dynamics simulations reveal that undergoes stepwise transition through sequential during process. Together functional analyses, our results suggest this arrangement allows facilitate passage via "relay" process, they establish framework for interpretation disease-related development future therapeutics. only exports cells. This study demonstrates uses mechanism transport, offering insights into potential therapeutic strategies XPR1-linked diseases.

Язык: Английский

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Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms

eLife, Год журнала: 2024, Номер 13

Опубликована: Янв. 22, 2024

Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature aging diseases, cells closely monitor as an indicator health. Given its central importance, it logical that would modulate in response to demand environmental cues, but there has been little exploration this question. We report the Sit4 phosphatase yeast increases potential, both by inducing electron transport chain phosphate starvation response. Indeed, similarly elevated also elicited simply or abrogation Pho85-dependent sensing pathway. This enhanced primarily driven unexpected activity ADP/ATP carrier. demonstrate connection between limitation enhancement observed primary immortalized mammalian well Drosophila. These data suggest subject stimuli intracellular signaling regulation raise possibility for therapeutic function even defective mitochondria.

Язык: Английский

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Homeostatic coordination of cellular phosphate uptake and efflux requires an organelle-based receptor for the inositol pyrophosphate IP8

Cell Reports, Год журнала: 2024, Номер 43(6), С. 114316 - 114316

Опубликована: Июнь 1, 2024

Язык: Английский

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Regenerative Cells in the Midgut of the Honey Bee Apis mellifera (Apidae: Apini) Queens with Different Ages

Brazilian Archives of Biology and Technology, Год журнала: 2024, Номер 67

Опубликована: Янв. 1, 2024

HIGHLIGHTS Honey bee queens have the long lifespan in colony. Queen midgut undergoes epithelial cell death with age. The epithelium renewal decreases queen Midgut stem cells differentiate without proliferation.

Язык: Английский

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Hazard assessment of nanoplastics is driven by their surface-functionalization. Effects in human-derived primary endothelial cells

The Science of The Total Environment, Год журнала: 2024, Номер 934, С. 173236 - 173236

Опубликована: Май 17, 2024

During plastic waste degradation into micro/nanoplastics (MNPLs) their physicochemical characteristics including surface properties (charge, functionalization, biocorona, etc.) can change, potentially affecting biological effects. This paper focuses on the functionalization of MNPLs to determine if it has a direct impact toxicokinetic and toxicodynamic interactions in human umbilical vein endothelial cells (HUVECs), at different exposure times. Pristine polystyrene nanoplastics (PS-NPLs), as well carboxylated (PS-C-NPLs) aminated (PS-A-NPLs) forms, all around 50 nm, were used wide battery toxicological assays. These assays encompassed evaluations cell viability, internalization, induction intracellular reactive oxygen species (iROS), genotoxicity. The experiments conducted concentration 100 μg/mL, chosen ensure high internalization rate across treatments while maintaining sub-toxic concentration. Our results show that PS-NPLs are internalized by HUVECs, but dynamic depends particle's functionalization. PS-C-NPLs modify morphology increasing its inner complexity/granularity. Regarding toxicity, only PS-A-NPLs reduced viability. Intracellular ROS was induced three time points. Genotoxic damage short exposures (2 h), not for 24 h. Overall, this study suggests effects PSNPLs HUVEC surface-dependent, highlighting relevance using human-derived primary target.

Язык: Английский

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Transport and InsP8 gating mechanisms of the human inorganic phosphate exporter XPR1

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 20, 2025

Inorganic phosphate (Pi) has essential metabolic and structural roles in living organisms. The Pi exporter, XPR1/SLC53A1, is critical for cellular homeostasis. When intercellular high, cells accumulate inositol pyrophosphate (1,5-InsP8), a signaling molecule required XPR1 function. Inactivating mutations lead to brain calcifications, causing neurological symptoms including movement disorders, psychosis, dementia. Here, cryo-electron microscopy structures of dimeric functional characterization delineate the substrate translocation pathway how InsP8 initiates transport. Binding XPR1, but not related polyphosphate InsP6, rigidifies intracellular SPX domains, with bridging dimers transmembrane domains. Locked this state, C-terminal tail sequestered, revealing entrance transport pathway, thus explaining obligate domain InsP8. Together, these findings advance our understanding activity expand opportunities rationalizing disease mechanisms therapeutic intervention. exporter maintenance levels. Here authors present cryo-EM that reveal binding 1,5-InsP8 its regulatory release.

Язык: Английский

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Structural mechanism underlying PHO1;H1-mediated phosphate transport in Arabidopsis

Nature Plants, Год журнала: 2025, Номер unknown

Опубликована: Янв. 21, 2025

Язык: Английский

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Toward understanding the cellular control of vertebrate mineralization: The potential role of mitochondria

Bone, Год журнала: 2024, Номер 185, С. 117112 - 117112

Опубликована: Май 1, 2024

Язык: Английский

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Transport and InsP₈activation mechanisms of the human inorganic phosphate exporter XPR1

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 5, 2024

Summary Inorganic phosphate (Pi) has essential metabolic and structural roles in living organisms. The Pi exporter, XPR1/SLC53A1, is critical for maintaining cellular homeostasis. When intercellular high, cells synthesize inositol pyrophosphate (1,5-InsP 8 ) – a signaling molecule that required XPR1 function. Inactivating mutations of lead to brain calcifications causing neurological symptoms include migraine, movements disorders, psychosis, dementia. Distinct cryo-electron microscopy structures dimeric functional characterization define the substrate translocation pathway delineate how binding InsP initiates transport cycle. rigidifies intracellular SPX domains with acting as bridge between dimers transmembrane domains. locked this state, C-terminal tail sequestered revealing entrance pathway, thus explaining obligate domain . Together, these findings advance our understanding activity expand opportunities rationalizing disease mechanisms therapeutic intervention.

Язык: Английский

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Subcellular quantitative imaging of metabolites at the organelle level

Nature Metabolism, Год журнала: 2023, Номер 5(9), С. 1446 - 1448

Опубликована: Сен. 7, 2023

Язык: Английский

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