Identification of surface residues on Niemann-Pick C2 essential for hydrophobic handoff of cholesterol to NPC1 in lysosomes

Michael L. Wang, Massoud Motamed, Rodney E. Infante, Lina Abi-Mosleh, Hyock Joo Kwon, Michael S. Brown, Joseph L. Goldstein

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

Water-soluble Niemann-Pick C2 (NPC2) and membrane-bound NPC1 are cholesterol-binding lysosomal proteins required for export of lipoprotein-derived cholesterol from lysosomes. The binding site in NPC1 is located inits N-terminal domain (NTD), which projects into the lysosomal lumen. Here we perform alanine-scanning mutagenesis to identify residues in NPC2 that are essential for transfer of cholesterol to NPC1(NTD). Transfer requires three residues that form a patch on the surface of NPC2. We previously identified a patch of residues on the surface of NPC1(NTD) that are required for transfer. We present a model in which these two surface patches on NPC2 and NPC1(NTD) interact, thereby opening an entry pore on NPC1(NTD) and allowing cholesterol to transfer without passing through the water phase. We refer to this transfer as a hydrophobic handoff and hypothesize that this handoff is essential for cholesterol export from lysosomes.

Original languageEnglish (US)
Pages (from-to)166-173
Number of pages8
JournalCell Metabolism
Volume12
Issue number2
DOIs
StatePublished - Aug 4 2010

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Lysosomes
Cholesterol
Water
Mutagenesis
Alanine
Binding Sites
Membranes

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Identification of surface residues on Niemann-Pick C2 essential for hydrophobic handoff of cholesterol to NPC1 in lysosomes. / Wang, Michael L.; Motamed, Massoud; Infante, Rodney E.; Abi-Mosleh, Lina; Kwon, Hyock Joo; Brown, Michael S.; Goldstein, Joseph L.

In: Cell Metabolism, Vol. 12, No. 2, 04.08.2010, p. 166-173.

Research output: Contribution to journalArticle

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AU - Motamed, Massoud

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AU - Abi-Mosleh, Lina

AU - Kwon, Hyock Joo

AU - Brown, Michael S.

AU - Goldstein, Joseph L.

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AB - Water-soluble Niemann-Pick C2 (NPC2) and membrane-bound NPC1 are cholesterol-binding lysosomal proteins required for export of lipoprotein-derived cholesterol from lysosomes. The binding site in NPC1 is located inits N-terminal domain (NTD), which projects into the lysosomal lumen. Here we perform alanine-scanning mutagenesis to identify residues in NPC2 that are essential for transfer of cholesterol to NPC1(NTD). Transfer requires three residues that form a patch on the surface of NPC2. We previously identified a patch of residues on the surface of NPC1(NTD) that are required for transfer. We present a model in which these two surface patches on NPC2 and NPC1(NTD) interact, thereby opening an entry pore on NPC1(NTD) and allowing cholesterol to transfer without passing through the water phase. We refer to this transfer as a hydrophobic handoff and hypothesize that this handoff is essential for cholesterol export from lysosomes.

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