NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes

Egress of lipoprotein-derived cholesterol from lysosomes requires two lysosomal proteins, polytopic membrane-bound Niemann-Pick C1 (NPC1) and soluble Niemann-Pick C2 (NPC2). The reason for this dual requirement is unknown. Previously, we showed that the soluble luminal N-terminal domain (NTD) of NPC...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2008-10, Vol.105 (40), p.15287-15292
Main Authors: Infante, Rodney E, Wang, Michael L, Radhakrishnan, Arun, Kwon, Hyock Joo, Brown, Michael S, Goldstein, Joseph L
Format: Article
Language:English
Subjects:
Biochemistry
Biological Sciences
Carrier Proteins - metabolism
Cholesterol
Cholesterol - metabolism
Cholesterols
Endosomes - metabolism
Gels
Genotype & phenotype
Glycoproteins - metabolism
Humans
Kinetics
Lipid Bilayers - metabolism
Lipids
Lipoproteins - metabolism
Liposomes
Liposomes - metabolism
Low density lipoprotein
Lysosomes
Lysosomes - metabolism
Membrane Glycoproteins - metabolism
Membranes
Metabolic diseases
Models, Biological
Niemann Pick diseases
Niemann-Pick Diseases - metabolism
Proteins
Scintillation counting
Sterols
Type C Niemann Pick disease
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Summary:Egress of lipoprotein-derived cholesterol from lysosomes requires two lysosomal proteins, polytopic membrane-bound Niemann-Pick C1 (NPC1) and soluble Niemann-Pick C2 (NPC2). The reason for this dual requirement is unknown. Previously, we showed that the soluble luminal N-terminal domain (NTD) of NPC1 (amino acids 25-264) binds cholesterol. This NTD is designated NPC1(NTD). We and others showed that soluble NPC2 also binds cholesterol. Here, we establish an in vitro assay to measure transfer of [³H]cholesterol between these two proteins and phosphatidylcholine liposomes. Whereas NPC2 rapidly donates or accepts cholesterol from liposomes, NPC1(NTD) acts much more slowly. Bidirectional transfer of cholesterol between NPC1(NTD) and liposomes is accelerated >100-fold by NPC2. A naturally occurring human mutant of NPC2 (Pro120Ser) fails to bind cholesterol and fails to stimulate cholesterol transfer from NPC1(NTD) to liposomes. NPC2 may be essential to deliver or remove cholesterol from NPC1, an interaction that links both proteins to the cholesterol egress process from lysosomes. These findings may explain how mutations in either protein can produce a similar clinical phenotype.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0807328105