Abstract
The Niemann–Pick C1 (NPC1) protein is the main protein involved in NPC disease, a fatal lysosomal lipid storage disease. NPC1, containing 1278 amino acids, is comprised of three lumenal domains (N-terminal, middle lumenal, C-terminal) and a transmembrane (TM) domain that contains a five helix bundle referred to as the sterol-sensing domain (SSD). The exact purpose of the SSD is not known, but it is believed that the SSD may bind cholesterol, either as a part of the lipid trafficking pathway or as part of a signaling mechanism. A recent cryo-EM structure has revealed an itraconazole binding site (IBS) in the SSD of human NPC1. Using this structural data, we constructed a model of cholesterol-bound wild-type (WT) and mutant P691S and performed molecular dynamics (MD) simulations of each cholesterol-bound protein. For WT NPC1, cholesterol migrates laterally, in the direction of the lipid bilayer. In the case of P691S, cholesterol is observed for the first time to migrate away from the SSD toward the N-terminal domain via a putative tunnel that connects the IBS with the lumenal domains. Structural features of the IBS are analyzed to identify the causes for different dynamical behavior between cholesterol-bound WT and cholesterol-bound P691S. The side chain of Ser691 in the P691S mutant introduces a hydrogen bond network that is not present in the WT protein. This change is likely responsible for the altered dynamical behavior observed in the P691S mutant and helps explain the disrupted cholesterol trafficking behavior observed in experiments.
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Cited by
10 articles.
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