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Gaucher disease-associated glucocerebrosidases show mutation-dependent chemical chaperoning profiles

Academic Article
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Overview

related to degree

  • Sawkar, Anupama, Ph.D. in Chemistry, Scripps Research 2000 - 2005

authors

  • Sawkar, Anupama
  • Adamski-Werner, S. L.
  • Cheng, W. C.
  • Wong, Chi-Huey
  • Beutler, Ernest
  • Zimmer, K. P.
  • Kelly, Jeffery

publication date

  • 2005

journal

  • Chemistry & Biology  Journal

abstract

  • Gaucher 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.

subject areas

  • Alkylation
  • Cells, Cultured
  • Gaucher Disease
  • Gene Expression Profiling
  • Glucose
  • Glucosides
  • Glucosylceramidase
  • Glycosylation
  • Humans
  • Kinetics
  • Lysosomes
  • Molecular Structure
  • Mutation
  • Protein Folding
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Identity

International Standard Serial Number (ISSN)

  • 1074-5521

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2005.09.007

PubMed ID

  • 16298303
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Additional Document Info

start page

  • 1235

end page

  • 1244

volume

  • 12

issue

  • 11

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