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PMID:18022370
| Citation |
Reczek, D, Schwake, M, Schröder, J, Hughes, H, Blanz, J, Jin, X, Brondyk, W, Van Patten, S, Edmunds, T and Saftig, P (2007) LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell 131:770-83 |
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| Abstract |
beta-glucocerebrosidase, the enzyme defective in Gaucher disease, is targeted to the lysosome independently of the mannose-6-phosphate receptor. Affinity-chromatography experiments revealed that the lysosomal integral membrane protein LIMP-2 is a specific binding partner of beta-glucocerebrosidase. This interaction involves a coiled-coil domain within the lumenal domain. beta-glucocerebrosidase activity and protein levels were severely decreased in LIMP-2-deficient mouse tissues. Analysis of fibroblasts and macrophages isolated from these mice indicated that the majority of beta-glucocerebrosidase was secreted. Missorting of beta-glucocerebrosidase was also evident in vivo, as protein and activity levels were significantly higher in sera from LIMP-2-deficient mice compared to wild-type. Reconstitution of LIMP-2 in LIMP-2-deficient fibroblasts led to a rescue of beta-glucocerebrosidase levels and distribution. LIMP-2 expression also led to lysosomal transport of a beta-glucocerebrosidase endoplasmic reticulum retention mutant. These data support a role for LIMP-2 as the mannose-6-phosphate-independent trafficking receptor for beta-glucocerebrosidase. |
| Links |
PubMed Online version:10.1016/j.cell.2007.10.018 |
| Keywords |
Amino Acid Sequence; Animals; Antigens, CD36/genetics; Antigens, CD36/metabolism; Cell Line; Endoplasmic Reticulum/metabolism; Fibroblasts/cytology; Fibroblasts/metabolism; Gaucher Disease/metabolism; Glucosylceramidase/genetics; Glucosylceramidase/metabolism; Humans; Lysosome-Associated Membrane Glycoproteins/genetics; Lysosome-Associated Membrane Glycoproteins/metabolism; Lysosomes/metabolism; Macrophages/cytology; Macrophages/metabolism; Mannosephosphates/genetics; Mannosephosphates/metabolism; Mice; Molecular Sequence Data; Protein Binding; Protein Structure, Secondary; Protein Transport; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Sequence Alignment |
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