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PreprintCited by 15Ion Transport and Channel RegulationParathyroid Disorders and TreatmentsIon channel regulation and function

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KIDINS220 and InsP8 safeguard the stepwise regulation of phosphate exporter XPR1

Open access
Wang, Xiaojie, Bai, Zhongjian, Wallis, Ciara, Wang, Huanchen, Han, Yaoyao, Jin, Ruitao, Lei, Mingguang, Yang, Tian, Gu, Chunfang, Jessen, Henning, Shears, Stephen, Sun, Yadong, Corry, Ben, Zhang, Yixiao·2025·Molecular Cell
DOI 10.1101/2025.01.17.633679

Preprint — published as 10.1016/j.molcel.2025.08.003

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Abstract

Summary: XPR1 is emerging as the only known inorganic phosphate (Pi) exporter in humans, critical for Pi homeostasis, with its activity stimulated by inositol pyrophosphate InsP8 and regulated by neuronal scaffold protein KIDINS220. Our structural studies reveal InsP8 specifically activates XPR1 in a stepwise manner, involving profound SPX domain movements. Each XPR1 subunit functions with four gating states, in which Pi permeates a constriction site via a “knock-kiss-kick” process. In contrast, KIDINS220 delicately stabilizes XPR1 in a closed conformation through multiple mechanisms, one of which involves trapping the XPR1 α1 helix—critical for InsP8 binding—within an interaction hub. InsP8 serves as a key to release KIDINS220’s restraint, reinforcing a “key-to-locks” mechanism to safeguard the stepwise activation. Additionally, our study provides direct structural insights into XPR1-associated neuronal disorders and highlights the evolutionary conservation and divergence among XPR1 orthologues, offering a comprehensive understanding of Pi homeostasis across species.

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Metadata

Authors
Wang, X., Bai, Z., Wallis, C., Wang, H., Han, Y., Jin, R., Lei, M., Yang, T., Gu, C., Jessen, H., Shears, S., Sun, Y., Corry, B., & Zhang, Y.
Affiliations
  • Chinese Academy of Sciences (CN)
  • Australian National University (AU)
  • National Institutes of Health (US)
  • Hangzhou Normal University (CN)
  • Eastern Hepatobiliary Surgery Hospital (CN)
  • University of Freiburg (DE)
  • ShanghaiTech University (CN)
Corresponding author
  • Shears, Stephen
  • Sun, Yadong
  • Corry, Ben
  • Zhang, Yixiao
ORCID
Venue
Molecular Cell
Publisher
openRxiv
Published
2025-01-19
Volume
85
Issue
17
Pages
3209-3224.e8
ISSN
1097-2765 (ISSN-L)
DOI
10.1101/2025.01.17.633679
OpenAlex
W4413583635
Cited by
15
References
1
Citations by year
2026: 10 · 2025: 5
FWCI
4.51
Type
journal article
Language
en
Open access
Licence
www.biorxiv.org/about/FAQ#license (vor)
Locations
  • Molecular Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • ANU Open Research (Australian National University) (acceptedVersion)
  • FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
Funders
  • National Computational Infrastructure
  • Australian Government
  • Ministry of Science and Technology of the People's Republic of China (2022ZD0207400)
  • Science and Technology Commission of Shanghai Municipality (19DZ2260400)
  • Government of Western Australia
  • National Institutes of Health
  • Australian Research Council (DP200100860)
  • Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
  • National Cancer Institute
  • National Institute of Environmental Health Sciences (ZIAES080046)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
XPR1, Kidins220, inositol pyrophosphates, phosphate homeostasis, SPX domain, protein-protein interaction, neuronal disorders, protein structure
MeSH terms
Xenotropic and Polytropic Retrovirus Receptor, Animals, Humans, Inositol Phosphates, Membrane Proteins, Models, Molecular, Phosphates, Protein Binding, Receptors, Cytoplasmic and Nuclear, Receptors, G-Protein-Coupled, HEK293 Cells

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