Characterization of the complex formed by beta-glucocerebrosidase and the lysosomal integral membrane protein type-2

Zunke F, Andresen L, Wesseler S, Groth J, Arnold P, Rothaug M, Mazzulli JR, Krainc D, Blanz J, Saftig P, Schwake M (2016)
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 113(14): 3791-3796.

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Abstract
The lysosomal integral membrane protein type-2 (LIMP-2) plays a pivotal role in the delivery of beta-glucocerebrosidase (GC) to lysosomes. Mutations in GC result in Gaucher's disease (GD) and are the major genetic risk factor for the development of Parkinson's disease (PD). Variants in the LIMP-2 gene cause action myoclonus-renal failure syndrome and also have been linked to PD. Given the importance of GC and LIMP-2 in disease pathogenesis, we studied their interaction sites in more detail. Our previous data demonstrated that the crystal structure of LIMP-2 displays a hydrophobic three-helix bundle composed of helices 4, 5, and 7, of which helix 5 and 7 are important for ligand binding. Here, we identified a similar helical motif in GC through surface potential analysis. Coimmunoprecipitation and immunofluorescence studies revealed a triple-helical interface region within GC as critical for LIMP-2 binding and lysosomal transport. Based on these findings, we generated a LIMP-2 helix 5-derived peptide that precipitated and activated recombinant wild-type and GD-associated N370S mutant GC in vitro. The helix 5 peptide fused to a cell-penetrating peptide also activated endogenous lysosomal GC and reduced alpha-synuclein levels, suggesting that LIMP-2-derived peptides can be used to activate endogenous as well as recombinant wild-type or mutant GC efficiently. Our data also provide a structural model of the LIMP-2/GC complex that will facilitate the development of GC chaperones and activators as potential therapeutics for GD, PD, and related synucleinopathies.
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Zunke F, Andresen L, Wesseler S, et al. Characterization of the complex formed by beta-glucocerebrosidase and the lysosomal integral membrane protein type-2. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2016;113(14):3791-3796.
Zunke, F., Andresen, L., Wesseler, S., Groth, J., Arnold, P., Rothaug, M., Mazzulli, J. R., et al. (2016). Characterization of the complex formed by beta-glucocerebrosidase and the lysosomal integral membrane protein type-2. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 113(14), 3791-3796. doi:10.1073/pnas.1514005113
Zunke, F., Andresen, L., Wesseler, S., Groth, J., Arnold, P., Rothaug, M., Mazzulli, J. R., Krainc, D., Blanz, J., Saftig, P., et al. (2016). Characterization of the complex formed by beta-glucocerebrosidase and the lysosomal integral membrane protein type-2. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 113, 3791-3796.
Zunke, F., et al., 2016. Characterization of the complex formed by beta-glucocerebrosidase and the lysosomal integral membrane protein type-2. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 113(14), p 3791-3796.
F. Zunke, et al., “Characterization of the complex formed by beta-glucocerebrosidase and the lysosomal integral membrane protein type-2”, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 113, 2016, pp. 3791-3796.
Zunke, F., Andresen, L., Wesseler, S., Groth, J., Arnold, P., Rothaug, M., Mazzulli, J.R., Krainc, D., Blanz, J., Saftig, P., Schwake, M.: Characterization of the complex formed by beta-glucocerebrosidase and the lysosomal integral membrane protein type-2. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 113, 3791-3796 (2016).
Zunke, Friederike, Andresen, Lisa, Wesseler, Sophia, Groth, Johann, Arnold, Philipp, Rothaug, Michelle, Mazzulli, Joseph R., Krainc, Dimitri, Blanz, Judith, Saftig, Paul, and Schwake, Michael. “Characterization of the complex formed by beta-glucocerebrosidase and the lysosomal integral membrane protein type-2”. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 113.14 (2016): 3791-3796.
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