IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58340-1.html
   My bibliography  Save this article

Cryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2

Author

Listed:
  • Jan Philipp Dobert

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU))

  • Jan-Hannes Schäfer

    (Osnabrück University)

  • Thomas Dal Maso

    (Pleinlaan 2
    Pleinlaan 2)

  • Priyadarshini Ravindran

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU))

  • Dustin J. E. Huard

    (Georgia Institute of Technology)

  • Eileen Socher

    (Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU))

  • Lisa A. Schildmeyer

    (Georgia Institute of Technology)

  • Raquel L. Lieberman

    (Georgia Institute of Technology)

  • Wim Versées

    (Pleinlaan 2
    Pleinlaan 2)

  • Arne Moeller

    (Osnabrück University
    Center of Cellular Nanoanalytic Osnabrück (CellNanOs); Osnabrück University)

  • Friederike Zunke

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU))

  • Philipp Arnold

    (Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU))

Abstract

Targeting proteins to their final cellular destination requires transport mechanisms and nearly all lysosomal enzymes reach the lysosome via the mannose-6-phosphate receptor pathway. One of the few known exceptions is the enzyme β-glucocerebrosidase (GCase) that requires the lysosomal integral membrane protein type-2 (LIMP-2) as a proprietary lysosomal transporter. Genetic variations in the GCase encoding gene GBA1 cause Gaucher’s disease (GD) and present the highest genetic risk factor to develop Parkinson’s disease (PD). Activators targeting GCase emerge as a promising therapeutic approach to treat GD and PD, with pre-clinical and clinical trials ongoing. In this study, we resolve the complex of GCase and LIMP-2 using cryo-electron microscopy with the aid of an engineered LIMP-2 shuttle and two GCase-targeted pro-macrobodies. We identify helix 5 and helix 7 of LIMP-2 to interact with a binding pocket in GCase, forming a mostly hydrophobic interaction interface supported by one essential salt bridge. Understanding the interplay of GCase and LIMP-2 on a structural level is crucial to identify potential activation sites and conceptualizing novel therapeutic approaches targeting GCase. Here, we unveil the protein structure of a mannose-6-phosphate-independent lysosomal transport complex and provide fundamental knowledge for translational clinical research to overcome GD and PD.

Suggested Citation

  • Jan Philipp Dobert & Jan-Hannes Schäfer & Thomas Dal Maso & Priyadarshini Ravindran & Dustin J. E. Huard & Eileen Socher & Lisa A. Schildmeyer & Raquel L. Lieberman & Wim Versées & Arne Moeller & Frie, 2025. "Cryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58340-1
    DOI: 10.1038/s41467-025-58340-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58340-1
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-58340-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Patrick Bryant & Gabriele Pozzati & Arne Elofsson, 2022. "Improved prediction of protein-protein interactions using AlphaFold2," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Mathieu Botte & Dongchun Ni & Stephan Schenck & Iwan Zimmermann & Mohamed Chami & Nicolas Bocquet & Pascal Egloff & Denis Bucher & Matilde Trabuco & Robert K. Y. Cheng & Janine D. Brunner & Markus A. , 2022. "Cryo-EM structures of a LptDE transporter in complex with Pro-macrobodies offer insight into lipopolysaccharide translocation," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    4. Saskia Heybrock & Kristiina Kanerva & Ying Meng & Chris Ing & Anna Liang & Zi-Jian Xiong & Xialian Weng & Young Ah Kim & Richard Collins & William Trimble & Régis Pomès & Gilbert G. Privé & Wim Annaer, 2019. "Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    5. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    6. Yuguang Zhao & Jingshan Ren & Sergi Padilla-Parra & Elizabeth E. Fry & David I. Stuart, 2014. "Lysosome sorting of β-glucocerebrosidase by LIMP-2 is targeted by the mannose 6-phosphate receptor," Nature Communications, Nature, vol. 5(1), pages 1-12, September.
    7. Patrick Bryant & Gabriele Pozzati & Arne Elofsson, 2022. "Author Correction: Improved prediction of protein-protein interactions using AlphaFold2," Nature Communications, Nature, vol. 13(1), pages 1-1, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Kazutoshi Tani & Ryo Kanno & Xuan-Cheng Ji & Itsusei Satoh & Yuki Kobayashi & Malgorzata Hall & Long-Jiang Yu & Yukihiro Kimura & Akira Mizoguchi & Bruno M. Humbel & Michael T. Madigan & Zheng-Yu Wang, 2023. "Rhodobacter capsulatus forms a compact crescent-shaped LH1–RC photocomplex," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    2. Patrick Bryant & Gabriele Pozzati & Wensi Zhu & Aditi Shenoy & Petras Kundrotas & Arne Elofsson, 2022. "Predicting the structure of large protein complexes using AlphaFold and Monte Carlo tree search," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Le Tracy Yu & Mark A. B. Kreutzberger & Thi H. Bui & Maria C. Hancu & Adam C. Farsheed & Edward H. Egelman & Jeffrey D. Hartgerink, 2024. "Exploration of the hierarchical assembly space of collagen-like peptides beyond the triple helix," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Hélène Bret & Jinmei Gao & Diego Javier Zea & Jessica Andreani & Raphaël Guerois, 2024. "From interaction networks to interfaces, scanning intrinsically disordered regions using AlphaFold2," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Zhiye Guo & Jian Liu & Jeffrey Skolnick & Jianlin Cheng, 2022. "Prediction of inter-chain distance maps of protein complexes with 2D attention-based deep neural networks," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    6. Z. Faidon Brotzakis & Shengyu Zhang & Mhd Hussein Murtada & Michele Vendruscolo, 2025. "AlphaFold prediction of structural ensembles of disordered proteins," Nature Communications, Nature, vol. 16(1), pages 1-9, December.
    7. Tânia F. Custódio & Maxime Killer & Dingquan Yu & Virginia Puente & Daniel P. Teufel & Alexander Pautsch & Gisela Schnapp & Marc Grundl & Jan Kosinski & Christian Löw, 2023. "Molecular basis of TASL recruitment by the peptide/histidine transporter 1, PHT1," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    8. Brooke M. Britton & Remy A. Yovanno & Sara F. Costa & Joshua McCausland & Albert Y. Lau & Jie Xiao & Zach Hensel, 2023. "Conformational changes in the essential E. coli septal cell wall synthesis complex suggest an activation mechanism," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    9. Yiying Yang & Haoxiang Chen & Robin A. Corey & Violette Morales & Yves Quentin & Carine Froment & Anne Caumont-Sarcos & Cécile Albenne & Odile Burlet-Schiltz & David Ranava & Phillip J. Stansfeld & Ju, 2023. "LptM promotes oxidative maturation of the lipopolysaccharide translocon by substrate binding mimicry," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    10. Patrick Bryant & Frank Noé, 2024. "Structure prediction of alternative protein conformations," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    11. Christoph Buhlheller & Theo Sagmeister & Christoph Grininger & Nina Gubensäk & Uwe B. Sleytr & Isabel Usón & Tea Pavkov-Keller, 2024. "SymProFold: Structural prediction of symmetrical biological assemblies," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    12. Caroline Servais & Victoria Vassen & Audrey Verhaeghe & Nina Küster & Elodie Carlier & Léa Phégnon & Aurélie Mayard & Nicolas Auberger & Stéphane Vincent & Xavier De Bolle, 2023. "Lipopolysaccharide biosynthesis and traffic in the envelope of the pathogen Brucella abortus," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    13. Devlina Chakravarty & Joseph W. Schafer & Ethan A. Chen & Joseph F. Thole & Leslie A. Ronish & Myeongsang Lee & Lauren L. Porter, 2024. "AlphaFold predictions of fold-switched conformations are driven by structure memorization," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    14. Ye Yuan & Lei Chen & Kexu Song & Miaomiao Cheng & Ling Fang & Lingfei Kong & Lanlan Yu & Ruonan Wang & Zhendong Fu & Minmin Sun & Qian Wang & Chengjun Cui & Haojue Wang & Jiuyang He & Xiaonan Wang & Y, 2024. "Stable peptide-assembled nanozyme mimicking dual antifungal actions," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    15. Ivica Odorčić & Mohamed Belal Hamed & Sam Lismont & Lucía Chávez-Gutiérrez & Rouslan G. Efremov, 2024. "Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    16. Surabhi Kokane & Ashutosh Gulati & Pascal F. Meier & Rei Matsuoka & Tanadet Pipatpolkai & Giuseppe Albano & Tin Manh Ho & Lucie Delemotte & Daniel Fuster & David Drew, 2025. "PIP2-mediated oligomerization of the endosomal sodium/proton exchanger NHE9," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    17. Stella Vitt & Simone Prinz & Martin Eisinger & Ulrich Ermler & Wolfgang Buckel, 2022. "Purification and structural characterization of the Na+-translocating ferredoxin: NAD+ reductase (Rnf) complex of Clostridium tetanomorphum," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    18. Pierre Azoulay & Joshua Krieger & Abhishek Nagaraj, 2024. "Old Moats for New Models: Openness, Control, and Competition in Generative Artificial Intelligence," NBER Chapters, in: Entrepreneurship and Innovation Policy and the Economy, volume 4, pages 7-46, National Bureau of Economic Research, Inc.
    19. Riya Shah & Thomas C. Panagiotou & Gregory B. Cole & Trevor F. Moraes & Brigitte D. Lavoie & Christopher A. McCulloch & Andrew Wilde, 2024. "The DIAPH3 linker specifies a β-actin network that maintains RhoA and Myosin-II at the cytokinetic furrow," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    20. Yashan Yang & Qianqian Shao & Mingcheng Guo & Lin Han & Xinyue Zhao & Aohan Wang & Xiangyun Li & Bo Wang & Ji-An Pan & Zhenguo Chen & Andrei Fokine & Lei Sun & Qianglin Fang, 2024. "Capsid structure of bacteriophage ΦKZ provides insights into assembly and stabilization of jumbo phages," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58340-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.