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NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a potential step in cholesterol egress from lysosomes.*
Author(s) -
Infante Rodney,
Brown Michael,
Goldstein Joseph
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.521.5
Subject(s) - npc1 , cholesterol , phosphatidylcholine , chemistry , reverse cholesterol transport , liposome , biochemistry , lipoprotein , microbiology and biotechnology , membrane , endosome , biology , phospholipid , receptor
The trafficking of lipoprotein‐derived cholesterol from lysosomes is dependent on the polytopic membrane‐bound Niemann‐Pick C1 (NPC1) and the soluble Niemann‐Pick C2 lysosomal proteins. The requirement for these proteins in the transport of cholesterol out of the lysosomes remains unclear. Previously, we demonstrated the ability of the N‐terminal luminal domain of NPC1, hereinafter called NPC1(NTD), to bind cholesterol with nM affinity. We and others also showed the ability of NPC2 to bind cholesterol with similar affinity. Recently, we established an in vitro assay detecting the movement of [ 3 H]cholesterol between these two proteins and model membranes. NPC2 readily transfers or receives [ 3 H]cholesterol to and from phosphatidylcholine liposomes, relative to NPC1(NTD). The bidirectional transport of [ 3 H]cholesterol between NPC1(NTD) and liposomes is accelerated over a 100 fold in the presence of NPC2. The naturally occurring mutant (Pro120Ser) form of NPC2 did not demonstrate significant cholesterol binding and had a reduction in the facilitation of cholesterol transport between NPC1(NTD) and liposomes. These studies begin to define the dual requirement of both proteins in the egress of lipoprotein‐derived cholesterol out of the lysosomes, thus explaining why mutations in either protein cause a similar clinical phenotype. *Infante, RE, et al. (2008) NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes. Proc Natl Acad Sci USA 105:15287‐15292.