Characterization of the complex formed by β-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)

Publication Type: Journal article

Publication year: 2016

Journal

Proceedings of the National Academy of Sciences of the United States of America National Academy of Sciences

Book Volume: 113

Pages Range: 3791-3796

Journal Issue: 14

DOI: 10.1073/pnas.1514005113

Abstract

The lysosomal integral membrane protein type-2 (LIMP-2) plays a pivotal role in the delivery of β-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 cellpenetrating peptide also activated endogenous lysosomal GC and reduced α-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.

Authors with CRIS profile

Friederike Zunke

Involved external institutions

Christian-Albrechts-Universität zu Kiel DE Germany (DE) Northwestern University US United States (USA) (US)

How to cite

APA:

Zunke, F., Andresen, L., Wesseler, S., Groth, J., Arnold, P., Rothaug, M.,... Schwake, M. (2016). Characterization of the complex formed by β-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. https://doi.org/10.1073/pnas.1514005113

MLA:

Zunke, Friederike, et al. "Characterization of the complex formed by β-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.

BibTeX: Download