Skip to main content

Multiple Surface Regions on the Niemann-Pick C2 Protein Facilitate Intracellular Cholesterol Transport.

Publication ,  Journal Article
McCauliff, LA; Xu, Z; Li, R; Kodukula, S; Ko, DC; Scott, MP; Kahn, PC; Storch, J
Published in: J Biol Chem
November 6, 2015

The cholesterol storage disorder Niemann-Pick type C (NPC) disease is caused by defects in either of two late endosomal/lysosomal proteins, NPC1 and NPC2. NPC2 is a 16-kDa soluble protein that binds cholesterol in a 1:1 stoichiometry and can transfer cholesterol between membranes by a mechanism that involves protein-membrane interactions. To examine the structural basis of NPC2 function in cholesterol trafficking, a series of point mutations were generated across the surface of the protein. Several NPC2 mutants exhibited deficient sterol transport properties in a set of fluorescence-based assays. Notably, these mutants were also unable to promote egress of accumulated intracellular cholesterol from npc2(-/-) fibroblasts. The mutations mapped to several regions on the protein surface, suggesting that NPC2 can bind to more than one membrane simultaneously. Indeed, we have previously demonstrated that WT NPC2 promotes vesicle-vesicle interactions. These interactions were abrogated, however, by mutations causing defective sterol transfer properties. Molecular modeling shows that NPC2 is highly plastic, with several intense positively charged regions across the surface that could interact favorably with negatively charged membrane phospholipids. The point mutations generated in this study caused changes in NPC2 surface charge distribution with minimal conformational changes. The plasticity, coupled with membrane flexibility, probably allows for multiple cholesterol transfer routes. Thus, we hypothesize that, in part, NPC2 rapidly traffics cholesterol between closely appositioned membranes within the multilamellar interior of late endosomal/lysosomal proteins, ultimately effecting cholesterol egress from this compartment.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

November 6, 2015

Volume

290

Issue

45

Start / End Page

27321 / 27331

Location

United States

Related Subject Headings

  • Vesicular Transport Proteins
  • Static Electricity
  • Protein Conformation
  • Point Mutation
  • Mutant Proteins
  • Mutagenesis, Site-Directed
  • Models, Molecular
  • Models, Biological
  • Mice
  • Membrane Lipids
 

Citation

APA
Chicago
ICMJE
MLA
NLM
McCauliff, L. A., Xu, Z., Li, R., Kodukula, S., Ko, D. C., Scott, M. P., … Storch, J. (2015). Multiple Surface Regions on the Niemann-Pick C2 Protein Facilitate Intracellular Cholesterol Transport. J Biol Chem, 290(45), 27321–27331. https://doi.org/10.1074/jbc.M115.667469
McCauliff, Leslie A., Zhi Xu, Ran Li, Sarala Kodukula, Dennis C. Ko, Matthew P. Scott, Peter C. Kahn, and Judith Storch. “Multiple Surface Regions on the Niemann-Pick C2 Protein Facilitate Intracellular Cholesterol Transport.J Biol Chem 290, no. 45 (November 6, 2015): 27321–31. https://doi.org/10.1074/jbc.M115.667469.
McCauliff LA, Xu Z, Li R, Kodukula S, Ko DC, Scott MP, et al. Multiple Surface Regions on the Niemann-Pick C2 Protein Facilitate Intracellular Cholesterol Transport. J Biol Chem. 2015 Nov 6;290(45):27321–31.
McCauliff, Leslie A., et al. “Multiple Surface Regions on the Niemann-Pick C2 Protein Facilitate Intracellular Cholesterol Transport.J Biol Chem, vol. 290, no. 45, Nov. 2015, pp. 27321–31. Pubmed, doi:10.1074/jbc.M115.667469.
McCauliff LA, Xu Z, Li R, Kodukula S, Ko DC, Scott MP, Kahn PC, Storch J. Multiple Surface Regions on the Niemann-Pick C2 Protein Facilitate Intracellular Cholesterol Transport. J Biol Chem. 2015 Nov 6;290(45):27321–27331.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

November 6, 2015

Volume

290

Issue

45

Start / End Page

27321 / 27331

Location

United States

Related Subject Headings

  • Vesicular Transport Proteins
  • Static Electricity
  • Protein Conformation
  • Point Mutation
  • Mutant Proteins
  • Mutagenesis, Site-Directed
  • Models, Molecular
  • Models, Biological
  • Mice
  • Membrane Lipids