Abstract
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).
Highlights
The Niemann Pick type C (NPC) proteins, NPC1 and NPC2, have received a great deal of attention in recent years, as they are involved in the lethal hereditary NPC disease, and as the NPC1 protein has been identified as being necessary for Ebola and Marburg virus infection [1,2]
When cholesterol is located in the NPC2 binding pocket, the same model exhibits RMS differences that fluctuate between 2 and 3 Å, in agreement with the behavior observed by Estiu et al [9]
molecular dynamics (MD) simulations indicate that the position of the cholesterol in the protein–protein complex affects the stability of the interface, as evidenced by the RMSD values of the models over 20 ns simulation time
Summary
The Niemann Pick type C (NPC) proteins, NPC1 and NPC2, have received a great deal of attention in recent years, as they are involved in the lethal hereditary NPC disease, and as the NPC1 protein has been identified as being necessary for Ebola and Marburg virus infection [1,2]. Cholesterol is likely transferred to NPC1’s membrane domain for subsequent biochemical processing [3] This mechanism of cholesterol transfer is supported by X-ray crystallography that shows the cholesterol’s isooctyl side chain buried deep inside the hydrophobic pocket of NPC2 with its 3β-hydroxyl group exposed at the protein’s surface [4]. NPC1(NTD) binds cholesterol in the opposite orientation: the 3β-hydroxyl group is buried in the binding pocket while the cholesterol’s isooctyl side chain is surface exposed [5] These findings led to the proposal of a “hydrophobic hand-off” or sliding model, in which cholesterol is transferred between NPC2 and NPC1(NTD) without exposure to water [6]
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