Gaucher Disease-Associated Glucocerebrosidases Show Mutation-Dependent Chemical Chaperoning Profiles
| Autor: | Jeffery W. Kelly, Klaus-Peter Zimmer, Chi-Huey Wong, Anu R. Sawkar, Wei-Chieh Cheng, Sara L. Adamski-Werner, Ernest Beutler |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Protein Folding
Cellular activity Glycosylation Alkylation Clinical Biochemistry Disease Biology medicine.disease_cause Biochemistry Glucosides Drug Discovery medicine Humans Molecular Biology Cells Cultured Therapeutic strategy Pharmacology Mutation Gaucher Disease Molecular Structure Gene Expression Profiling Endoplasmic reticulum General Medicine Pharmacological chaperone Kinetics Glucose Glucosylceramidase Molecular Medicine Chemical chaperone Lysosomes Glucocerebrosidase medicine.drug |
| Zdroj: | Chemistry & Biology. 12:1235-1244 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2005.09.007 |
| Popis: | SummaryGaucher disease is a lysosomal storage disorder caused by deficient glucocerebrosidase activity. We have previously shown that the cellular activity of the most common Gaucher disease-associated glucocerebrosidase variant, N370S, is increased when patient-derived cells are cultured with the chemical chaperone N-nonyl-deoxynojirimycin. Chemical chaperones stabilize proteins against misfolding, enabling their trafficking from the endoplasmic reticulum. Herein, the generality of this therapeutic strategy is evaluated with other glucocerebrosidase variants and with additional candidate chemical chaperones. Improved chemical chaperones are identified for N370S glucocerebrosidase. Moreover, we demonstrate that G202R, a glucocerebrosidase variant that is known to be retained in the endoplasmic reticulum, is also amenable to chemical chaperoning. The L444P variant is not chaperoned by any of the active site-directed molecules tested, likely because this mutation destabilizes a domain distinct from the catalytic domain. |
| Databáze: | OpenAIRE |
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