Simulations of NPC1(NTD):NPC2 Protein Complex Reveal Cholesterol Transfer Pathways.
Int J Mol Sci
; 19(9)2018 Sep 04.
Article
en En
| MEDLINE
| ID: mdl-30181526
ABSTRACT
The Niemann Pick type C (NPC) proteins, NPC1 and NPC2, are involved in the lysosomal storage disease, NPC disease. The formation of a NPC1â»NPC2 proteinâ»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)â»NPC2 proteinâ»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).
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Glicoproteínas de Membrana
/
Glicoproteínas
/
Proteínas Portadoras
/
Colesterol
Límite:
Humans
Idioma:
En
Revista:
Int J Mol Sci
Año:
2018
Tipo del documento:
Article
País de afiliación:
Eslovenia