title: A critical histidine residue within LIMP-2 mediates pH sensitive binding to its ligand β-glucocerebrosidase.
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.
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098, Kiel, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Zachos
authors.forename: Judith
authors.initials: J
authors.lastname: Blanz
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Michael
authors.initials: M
authors.lastname: Schwake
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018389:Codon, Nonsense; D011992:Endosomes / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005962:Glucosylceramidase / Q000378:metabolism*; D006367:HeLa Cells; D006639:Histidine / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051907:Lysosomal Membrane Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D051116:Receptors, Scavenger / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D004791:Enzyme Inhibitors; D051907:Lysosomal Membrane Proteins; D018942:Macrolides; D051116:Receptors, Scavenger; C074299:SCARB2 protein, human; D006639:Histidine; C040929:bafilomycin A1; D005962:Glucosylceramidase; D025262:Vacuolar Proton-Translocating ATPases