+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Simulations of NPC1(NTD):NPC2 Protein Complex Reveal Cholesterol Transfer Pathways

Simulations of NPC1(NTD):NPC2 Protein Complex Reveal Cholesterol Transfer Pathways

International Journal of Molecular Sciences 19(9)

The Niemann Pick type C (NPC) proteins, NPC1 and NPC2, are involved in the lysosomal storage disease, NPC disease. The formation of a NPC1⁻NPC2 protein⁻protein complex is believed to be necessary for the transfer of cholesterol and lipids out of the late endosomal (LE)/lysosomal (Lys) compartments. Mutations in either NPC1 or NPC2 can lead to an accumulation of cholesterol and lipids in the LE/Lys, the primary phenotype of the NPC disease. We investigated the NPC1(NTD)⁻NPC2 protein⁻protein complex computationally using two putative binding interfaces. A combination of molecular modeling and molecular dynamics simulations reveals atomic details that are responsible for interface stability. Cholesterol binding energies associated with each of the binding pockets for the two models are calculated. Analyses of the cholesterol binding in the two models support bidirectional ligand transfer when a particular interface is established. Based on the results, we propose that, depending on the location of the cholesterol ligand, a dynamical interface between the NPC2 and NPC1(NTD) proteins exists. Structural features of a particular interface can lower the energy barrier and stabilize the passage of the cholesterol substrate from NPC2 to NPC1(NTD).

(PDF emailed within 0-6 h: $19.90)

Accession: 065917607

Download citation: RISBibTeXText

PMID: 30181526

DOI: 10.3390/ijms19092623

Related references

Glycosphingolipid - cholesterol abnormalities in NPC2 - deficient neurons appear equivalent to those occurring in neurons lacking NPC1, suggesting NPC1 - NPC2 molecular cooperation. Society for Neuroscience Abstract Viewer & Itinerary Planner : Abstract No 537 15, 2003

NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes. Proceedings of the National Academy of Sciences of the United States of America 105(40): 15287-15292, 2008

Computational studies of the cholesterol transport between NPC2 and the N-terminal domain of NPC1 (NPC1(NTD)). Biochemistry 52(39): 6879-6891, 2014

Ultrastructural Similarity of Storage Bodies in Neurons Lacking NPC1, NPC2, or Both Proteins Suggest NPC1-NPC2 Molecular Co-operativity in Lipid Trafficking. Microscopy and Microanalysis 10(S02): 1468-1469, 2004

Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2. Proceedings of the National Academy of Sciences of the United States of America 113(36): 10079-10084, 2018

NPC1 and NPC2 regulate cellular cholesterol homeostasis through generation of low density lipoprotein cholesterol-derived oxysterols. Journal of Biological Chemistry 278(28): 25517-25525, 2003

NPC1/NPC2 function as a tag team duo to mobilize cholesterol. Proceedings of the National Academy of Sciences of the United States of America 105(40): 15223-4, 2008

A role for NPC1 and NPC2 in intestinal cholesterol absorption--the hypothesis gutted. Biochemical Journal 408(1): E1-E3, 2007

Insights into the Molecular Mechanisms of Cholesterol Binding to the NPC1 and NPC2 Proteins. Advances in Experimental Medicine and Biology 1135: 139-160, 2019

Do mammalian NPC1 and NPC2 play a role in intestinal cholesterol absorption?. Biochemical Journal 408(1): 1-5, 2007

Quantitative role of LAL, NPC2, and NPC1 in lysosomal cholesterol processing defined by genetic and pharmacological manipulations. Journal of Lipid Research 52(4): 688-698, 2011

Niemann-Pick type C disease: a QM/MM study of conformational changes in cholesterol in the NPC1(NTD) and NPC2 binding pockets. Biochemistry 53(41): 6603-6614, 2015

Physiological and coordinate downregulation of the NPC1 and NPC2 genes are associated with the sequestration of LDL-derived cholesterol within endocytic compartments. Journal of Cellular Biochemistry 108(5): 1102-1116, 2010

Cholesterol overload promotes morphogenesis of a Niemann-Pick C (NPC)-like compartment independent of inhibition of NPC1 or HE1/NPC2 function. Journal of Biological Chemistry 276(49): 46414-46421, 2001

FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts. Faseb Journal 31(4): 1719-1730, 2017