Abstract
The lysosomal membrane protein type 2 is a novel identified lysosomal sorting receptor for β-glucocerebrosidase (GC). Mutations in both genes underlie human pathologies causing action myoclonus-renal failure syndrome (AMRF) and Gaucher disease (GD), respectively. We now demonstrate that the lumenal acidification mediated by the vacuolar (H(+) )-ATPase triggers the dissociation of LIMP-2 and GC in late endosomal/lysosomal compartments. Moreover, we identified a single histidine residue in LIMP-2 that is necessary for LIMP-2 and GC binding. This residue is in close proximity to a proposed coiled-coil domain, which determines the binding to GC and may function as a critical pH sensor.
© 2012 John Wiley & Sons A/S.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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COS Cells
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Cells, Cultured
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Chlorocebus aethiops
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Codon, Nonsense
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Endosomes / enzymology
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Endosomes / metabolism
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Enzyme Inhibitors / pharmacology
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Fibroblasts / metabolism
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Glucosylceramidase / metabolism*
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HeLa Cells
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Histidine / chemistry*
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Humans
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Hydrogen-Ion Concentration
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Lysosomal Membrane Proteins / chemistry*
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Lysosomal Membrane Proteins / genetics*
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Lysosomal Membrane Proteins / metabolism
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Lysosomes / enzymology
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Lysosomes / metabolism
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Macrolides / pharmacology
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Mice
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Molecular Sequence Data
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Mutation, Missense
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Myoclonic Epilepsies, Progressive / genetics
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Protein Binding / genetics
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Receptors, Scavenger / chemistry*
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Receptors, Scavenger / genetics*
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Receptors, Scavenger / metabolism
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Vacuolar Proton-Translocating ATPases / antagonists & inhibitors
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Vacuolar Proton-Translocating ATPases / metabolism
Substances
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Codon, Nonsense
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Enzyme Inhibitors
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Lysosomal Membrane Proteins
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Macrolides
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Receptors, Scavenger
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SCARB2 protein, human
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Histidine
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bafilomycin A1
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Glucosylceramidase
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Vacuolar Proton-Translocating ATPases