The integrity of a cholesterol-binding pocket in Niemann-Pick C2 protein is necessary to control lysosome cholesterol levels.

Journal Article (Journal Article)

The neurodegenerative disease Niemann-Pick Type C2 (NPC2) results from mutations in the NPC2 (HE1) gene that cause abnormally high cholesterol accumulation in cells. We find that purified NPC2, a secreted soluble protein, binds cholesterol specifically with a much higher affinity (K(d) = 30-50 nM) than previously reported. Genetic and biochemical studies identified single amino acid changes that prevent both cholesterol binding and the restoration of normal cholesterol levels in mutant cells. The amino acids that affect cholesterol binding surround a hydrophobic pocket in the NPC2 protein structure, identifying a candidate sterol-binding location. On the basis of evolutionary analysis and mutagenesis, three other regions of the NPC2 protein emerged as important, including one required for efficient secretion.

Full Text

Duke Authors

Cited Authors

  • Ko, DC; Binkley, J; Sidow, A; Scott, MP

Published Date

  • March 4, 2003

Published In

Volume / Issue

  • 100 / 5

Start / End Page

  • 2518 - 2525

PubMed ID

  • 12591949

Pubmed Central ID

  • PMC151373

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0530027100


  • eng

Conference Location

  • United States