Discovery of oxysterol-derived pharmacological chaperones for NPC1: implication for the existence of second sterol-binding site.

Abstract

Niemann-Pick type C1 (NPC1) is a polytopic endosomal membrane protein required for efflux of LDL-derived cholesterol from endosomes, and mutations of this protein are associated with Niemann-Pick disease type C, a fatal neurodegenerative disease. At least one prevalent mutation (I1061T) has been shown to cause a folding defect, which results in failure of endosomal localization, leading to a loss-of-function phenotype. Here, we show that several oxysterols and their derivatives act as pharmacological chaperones; binding of these compounds to I1061T NPC1 corrects the localization/maturation defect of the mutant protein. Further, these compounds alleviate intracellular cholesterol accumulation in patient-derived fibroblasts, suggesting that they may have therapeutic potential. These oxysterol derivatives bind to a domain of NPC1 that is different from the known N-terminal sterol-binding domain; i.e., there is an additional sterol-binding site on NPC1.

• Authors: Kenji Ohgane, Fumika Karaki, Kosuke Dodo, Yuichi Hashimoto
• Journal: Chemistry & biology (Chem Biol) Vol. 20 Issue 3 Pg. 391-402 (Mar 21 2013) ISSN: 1879-1301 [Electronic] United States
• PMID: 23521797 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Carrier Proteins
• Hydroxycholesterols
• Intracellular Signaling Peptides and Proteins
• Membrane Glycoproteins
• NPC1 protein, human
• Niemann-Pick C1 Protein
• 25-hydroxycholesterol

Topics

• Binding Sites
• Carrier Proteins (chemistry, genetics, metabolism)
• Drug Discovery
• Fibroblasts (drug effects, metabolism, pathology)
• HEK293 Cells
• Humans
• Hydroxycholesterols (chemistry, metabolism, pharmacology)
• Intracellular Signaling Peptides and Proteins
• Intracellular Space (drug effects, metabolism)
• Membrane Glycoproteins (chemistry, genetics, metabolism)
• Mutation
• Niemann-Pick C1 Protein
• Niemann-Pick Disease, Type C (pathology)
• Oxidation-Reduction
• Protein Folding (drug effects)
• Protein Structure, Tertiary
• Protein Transport
• Structure-Activity Relationship