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Conformational cycle of human polyamine transporter ATP13A2

Author

Listed:
  • Jianqiang Mu

    (Southern University of Science and Technology)

  • Chenyang Xue

    (Southern University of Science and Technology)

  • Lei Fu

    (Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University)

  • Zongjun Yu

    (Southern University of Science and Technology)

  • Minhan Nie

    (Sun Yat-sen University, No.132 Wai Huan Dong Lu, Guangzhou Higher Education Mega Center)

  • Mengqi Wu

    (Southern University of Science and Technology)

  • Xinmeng Chen

    (Southern University of Science and Technology)

  • Kun Liu

    (Southern University of Science and Technology)

  • Ruiqian Bu

    (Southern University of Science and Technology)

  • Ying Huang

    (Southern University of Science and Technology)

  • Baisheng Yang

    (Southern University of Science and Technology)

  • Jianming Han

    (Southern University of Science and Technology)

  • Qianru Jiang

    (Southern University of Science and Technology)

  • Kevin C. Chan

    (Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University)

  • Ruhong Zhou

    (Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University)

  • Huilin Li

    (Sun Yat-sen University, No.132 Wai Huan Dong Lu, Guangzhou Higher Education Mega Center
    Sun Yat-sen University)

  • Ancheng Huang

    (Southern University of Science and Technology)

  • Yong Wang

    (Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University
    The Provincial International Science and Technology Cooperation Base on Engineering Biology, International Campus of Zhejiang University)

  • Zhongmin Liu

    (Southern University of Science and Technology)

Abstract

Dysregulation of polyamine homeostasis strongly associates with human diseases. ATP13A2, which is mutated in juvenile-onset Parkinson’s disease and autosomal recessive spastic paraplegia 78, is a transporter with a critical role in balancing the polyamine concentration between the lysosome and the cytosol. Here, to better understand human ATP13A2-mediated polyamine transport, we use single-particle cryo-electron microscopy to solve high-resolution structures of human ATP13A2 in six intermediate states, including the putative E2 structure for the P5 subfamily of the P-type ATPases. These structures comprise a nearly complete conformational cycle spanning the polyamine transport process and capture multiple substrate binding sites distributed along the transmembrane regions, suggesting a potential polyamine transport pathway. Integration of high-resolution structures, biochemical assays, and molecular dynamics simulations allows us to obtain a better understanding of the structural basis of how hATP13A2 transports polyamines, providing a mechanistic framework for ATP13A2-related diseases.

Suggested Citation

  • Jianqiang Mu & Chenyang Xue & Lei Fu & Zongjun Yu & Minhan Nie & Mengqi Wu & Xinmeng Chen & Kun Liu & Ruiqian Bu & Ying Huang & Baisheng Yang & Jianming Han & Qianru Jiang & Kevin C. Chan & Ruhong Zho, 2023. "Conformational cycle of human polyamine transporter ATP13A2," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37741-0
    DOI: 10.1038/s41467-023-37741-0
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    References listed on IDEAS

    as
    1. Ping Li & Kaituo Wang & Nina Salustros & Christina Grønberg & Pontus Gourdon, 2021. "Structure and transport mechanism of P5B-ATPases," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
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    3. Arthur Laganowsky & Eamonn Reading & Timothy M. Allison & Martin B. Ulmschneider & Matteo T. Degiacomi & Andrew J. Baldwin & Carol V. Robinson, 2014. "Membrane proteins bind lipids selectively to modulate their structure and function," Nature, Nature, vol. 510(7503), pages 172-175, June.
    4. Yoshiyuki Norimatsu & Kazuya Hasegawa & Nobutaka Shimizu & Chikashi Toyoshima, 2017. "Protein–phospholipid interplay revealed with crystals of a calcium pump," Nature, Nature, vol. 545(7653), pages 193-198, May.
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