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

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

Published: Jan. 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.

Language: Английский

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

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

Published: March 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.

Language: Английский

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A small signaling domain controls PPIP5K phosphatase activity in phosphate homeostasis

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

Published: Feb. 19, 2025

Abstract Inositol pyrophosphates (PP-InsPs) are eukaryotic nutrient messengers. The N-terminal kinase domain of diphosphoinositol pentakisphosphate (PPIP5K) generates the messenger 1,5-InsP 8 , C-terminal phosphatase catalyzes PP-InsP breakdown. balance between and activities regulates levels. Here, we present crystal structures apo substrate-bound PPIP5K from S. cerevisiae (ScVip1 PD ). ScVip1 is a phytase-like inositol 1-pyrophosphate histidine with two conserved catalytic motifs. enzyme has strong preference for inhibited by inorganic phosphate. It contains an α-helical insertion stabilized structural Zn 2+ binding site, unique GAF that channels substrate to active site. Mutations alter restrict movement domain, or change channel’s charge inhibit activity in vitro, Arabidopsis VIH2 planta . Our work reveals structure, enzymatic mechanism regulation phosphatases.

Language: Английский

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Structural basis of phosphate export by human XPR1

Cell Research, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 28, 2025

Language: Английский

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Synergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphate

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

Published: March 24, 2025

Inorganic phosphate (Pi) is essential for life, and its intracellular levels must be tightly regulated to avoid toxicity. XPR1, the sole known exporter, critical maintaining this balance. Here we report cryo-EM structures of human XPR1-KIDINS220 complex in substrate-free closed substrate-bound outward-open states, as well an XPR1 mutant a inward-facing state. In presence inositol hexaphosphate (InsP6) phosphate, adopts conformation, with InsP6 binding SPX domain juxtamembrane regions, indicating active export. Without or InsP6, closes, transmembrane helix 9 blocking outward cavity C-terminal loop obstructing cavity. alone remains even InsP6. Functional mutagenesis shows that whose vary Pi availability, works KIDINS220 regulate activity. These insights into regulation may aid developing therapies ovarian cancer. exporter human. Here, authors provide structural evidence on how pyrophosphate synergistically conformation efflux activity XPR1.

Language: Английский

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Transport and InsP₈activation mechanisms of the human inorganic phosphate exporter XPR1

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

Published: Oct. 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.

Language: Английский

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

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

Published: Aug. 20, 2024

Abstract XPR1 is the only known protein responsible for transporting inorganic phosphate (Pi) out of cells, a function conserved from yeast to mammals. Human variants lead cerebral calcium-phosphate deposition, which are associated with hereditary neurodegenerative disorder as primary familial brain calcification (PFBC). Here, we present cryo-EM structure human in both its Pi-unbound form and various Pi-bound states. features 10 transmembrane α-helices that an ion channel-like architecture. Multiple Pi recognition sites arranged along channel, facilitating transport. Two arginine residues, subject pathogenic mutation PFBC families, line translocation channel serve bind ion. Clinically linked mutations these arginines impair XPR1’s transport activity. To gain dynamic insights into mechanism, conducted molecular dynamics simulations. The simulations reveal undergoes stepwise transition through sequential during process. Together functional analyses, our results suggest arrangement likely enable use “relay” process facilitate passage they establish framework interpretation disease-related development future therapeutics. One Sentence Summary Combined cryo-EM, studies demonstrate employs mechanism export cells

Language: Английский

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The putative polyamine transporter Shp2 facilitates phosphate export in an Xpr1-independent manner and contributes to high phosphate tolerance

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 108056 - 108056

Published: Dec. 1, 2024

Language: Английский

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

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 29, 2024

XPR1 is the only known protein that transports inorganic phosphate (Pi) out of cells, and function conserved across species from yeast to mammals^1-4. Human variants lead cerebral calcium-phosphate deposition, which are associated with a neurodegenerative disorder as primary familial brain calcification (PFBC)⁵. Here, we present Cryo-EM structure human bound Pi ions. contains 10 transmembrane α-helices, forming an ion channel-like architecture recognizes Two arginine residues, subject pathogenic mutation in PFBC families, line translocation channel serve bind Clinically linked mutations these residues impair transport activity XPR1. To track movement ions within channel, capture mutant alternative conformation. It reveals rearrangement intrahelical hydrogen bonds between channel-lining tryptophan two Pi-binding residues. This links recognition transport, by means flipping residue propel through channel. Our results provide mechanistic understanding how cell membrane, they establish framework for interpreting disease-related development future therapeutics.

Language: Английский

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Encapsulation of Inositol Hexakisphosphate with Chitosan via Gelation to Facilitate Cellular Delivery and Programmed Cell Death in Human Breast Cancer Cells

Bioengineering, Journal Year: 2024, Volume and Issue: 11(9), P. 931 - 931

Published: Sept. 17, 2024

Inositol hexakisphosphate (InsP

Language: Английский

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