title: 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.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan. ohgane@me.com
authors.forename: Kenji
authors.initials: K
authors.lastname: Ohgane
authors.forename: Fumika
authors.initials: F
authors.lastname: Karaki
authors.forename: Kosuke
authors.initials: K
authors.lastname: Dodo
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D055808:Drug Discovery; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000473:pathology; D010084:Oxidation-Reduction; D017510:Protein Folding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D013329:Structure-Activity Relationship
chemical_list: D002352:Carrier Proteins; D006888:Hydroxycholesterols; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; C007997:25-hydroxycholesterol