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Endoplasmic reticulum Ca(2+) increases enhance mutant glucocerebrosidase proteostasis

Academic Article
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Overview

related to degree

  • Ong, Derrick, Ph.D. in Chemical Biology, Scripps Research 2007 - 2011

authors

  • Ong, Derrick
  • Mu, T. W.
  • Palmer, A. E.
  • Kelly, Jeffery

publication date

  • 2010

journal

  • Nature Chemical Biology  Journal

abstract

  • Altering intracellular calcium levels is known to partially restore mutant enzyme homeostasis in several lysosomal storage diseases, but why? We hypothesized that endoplasmic reticulum (ER) calcium increases enhance the folding, trafficking and function of these mutant misfolding- and degradation-prone lysosomal enzymes by increasing chaperone function. Here we report that increasing ER calcium levels by reducing ER calcium efflux through the ryanodine receptor, using antagonists or RNAi, or by promoting ER calcium influx by SERCA2b overexpression enhances mutant glucocerebrosidase (GC) homeostasis in cells derived from individuals with Gaucher's disease. Post-translational regulation of the calnexin folding pathway by an elevated ER calcium concentration seems to enhance the capacity of this chaperone system to fold mutant misfolding-prone enzymes, increasing the folded mutant GC population that can engage the trafficking receptor at the expense of ER-associated degradation, increasing the lysosomal GC concentration and activity.

subject areas

  • Amino Acid Substitution
  • Calcium
  • Calcium Channel Blockers
  • Diltiazem
  • Endoplasmic Reticulum
  • Gaucher Disease
  • Glucosylceramidase
  • Humans
  • Lysosomes
  • Protein Folding
  • Protein Processing, Post-Translational
  • Ryanodine Receptor Calcium Release Channel
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Vasodilator Agents
  • Verapamil
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Identity

PubMed Central ID

  • PMC2873071

International Standard Serial Number (ISSN)

  • 1552-4450

Digital Object Identifier (DOI)

  • 10.1038/nchembio.368

PubMed ID

  • 20453863
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Additional Document Info

start page

  • 424

end page

  • 432

volume

  • 6

issue

  • 6

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