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Lysosome sorting of β-glucocerebrosidase by LIMP-2 is targeted by the mannose 6-phosphate receptor

Author

Listed:
  • Yuguang Zhao

    (University of Oxford, The Henry Wellcome Building for Genomic Medicine)

  • Jingshan Ren

    (University of Oxford, The Henry Wellcome Building for Genomic Medicine)

  • Sergi Padilla-Parra

    (University of Oxford, The Henry Wellcome Building for Genomic Medicine)

  • Elizabeth E. Fry

    (University of Oxford, The Henry Wellcome Building for Genomic Medicine)

  • David I. Stuart

    (University of Oxford, The Henry Wellcome Building for Genomic Medicine)

Abstract

The integral membrane protein LIMP-2 has been a paradigm for mannose 6-phosphate receptor (MPR) independent lysosomal targeting, binding to β-glucocerebrosidase (β-GCase) and directing it to the lysosome, before dissociating in the late-endosomal/lysosomal compartments. Here we report structural results illuminating how LIMP-2 binds and releases β-GCase according to changes in pH, via a histidine trigger, and suggesting that LIMP-2 localizes the ceramide portion of the substrate adjacent to the β-GCase catalytic site. Remarkably, we find that LIMP-2 bears P-Man9GlcNAc2 covalently attached to residue N325, and that it binds MPR, via mannose 6-phosphate, with a similar affinity to that observed between LIMP-2 and β-GCase. The binding sites for β-GCase and the MPR are functionally separate, so that a stable ternary complex can be formed. By fluorescence lifetime imaging microscopy, we also demonstrate that LIMP-2 interacts with MPR in living cells. These results revise the accepted view of LIMP-2–β-GCase lysosomal targeting.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5321
    DOI: 10.1038/ncomms5321
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