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

Li, Xingyao; Kirkpatrick, Regan B.; Wang, Xiaodong; Tucker, Charles J.; Shukla, Anuj; Jessen, Henning J.; Wang, Huanchen; Shears, Stephen B.; Gu, Chunfang

doi:10.1016/j.celrep.2024.114316

Cell Reports

2024

DOI: 10.1016/j.celrep.2024.114316

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

Xingyao Li,

Regan B. Kirkpatrick,

Xiaodong Wang

et al.

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2024

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Cited by 3 publications

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

Zhang,

Chen,

Guan

et al. 2024

Preprint

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

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

Zhang,

Chen,

Guan

et al. 2024

Preprint

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A small signaling domain controls PPIP5K phosphatase activity in phosphate homeostasis

Raia,

Lee,

Bartsch

et al. 2024

Preprint

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Inositol pyrophosphates are highly phosphorylated nutrient messengers. The final step of their biosynthesis is catalyzed by diphosphoinositol pentakisphosphate kinase (PPIP5K) enzymes, which are conserved among fungi, plants, and animals. PPIP5Ks contain an N-terminal kinase domain that generates the active messenger 1,5-InsP8 and a C-terminal phosphatase domain that participates in PP-InsP catabolism. The balance between kinase and phosphatase activities controls the cellular levels and signaling capacity of 1,5-InsP8. Here, we present crystal structures of the apo and substrate-bound Vip1 phosphatase domain from S. cerevisiae (ScVip1PD). ScVip1PD is a phytase-like inositol 1-pyrophosphate phosphatase with two conserved histidine phosphatase catalytic motifs. The enzyme has a strong preference for 1,5-InsP8 and is inhibited by inorganic phosphate. ScVip1PD has an alpha-helical insertion domain stabilized by a structural Zn2+ binding site, and a unique GAF domain that exists in an open and closed state, allowing channeling of the 1,5-InsP8 substrate to the active site. Mutations that alter the active site, that restrict the movement of the GAF domain or that modify the charge of the substrate channel significantly inhibit the activity of the yeast enzyme in vitro, and the function of the Arabidopsis PPIP5K VIH2 in planta. Structural analyses of full-length PPIP5Ks suggest that the kinase and phosphatase are independent enzymatic modules. Taken together, our work reveals the structure, enzymatic mechanism and regulation of eukaryotic PPIP5K phosphatases.

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

Zhu,

Yaggi,

Jork

et al. 2024

Preprint

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Inorganic phosphate (Pi) has essential metabolic and structural roles in living organisms. The Pi exporter, XPR1/SLC53A1, is critical for maintaining cellular Pi homeostasis. When intercellular Pi is high, cells synthesize inositol pyrophosphate (1,5-InsP8) - a signaling molecule that is required for XPR1 function. Inactivating mutations of XPR1 lead to brain calcifications causing neurological symptoms that include migraine, movements disorders, psychosis, and dementia. Distinct cryo-electron microscopy structures of dimeric XPR1 and functional characterization define the substrate translocation pathway and delineate how binding of InsP8initiates the transport cycle. InsP8binding rigidifies the intracellular SPX domains with InsP8acting as a bridge between dimers and the SPX and transmembrane domains. When locked in this state, the C-terminal tail is sequestered revealing the entrance to the transport pathway, thus explaining the obligate roles of the SPX domain and InsP8. Together, these findings advance our understanding of XPR1 transport activity and expand opportunities for rationalizing disease mechanisms and therapeutic intervention.

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

Cited by 3 publications

References 49 publications

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

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

A small signaling domain controls PPIP5K phosphatase activity in phosphate homeostasis

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

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