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

Yuguang Zhao, Jingshan Ren, Sergi Padilla-Parra, Elizabeth E. Fry and David I. Stuart ()
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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

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5321

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