Cholesterol Transport in Wild-Type NPC1 and P691S: Molecular Dynamics Simulations Reveal Changes in Dynamical Behavior.

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 chol

SUBMITTER: Elghobashi-Meinhardt N 

PROVIDER: S-EPMC7215871 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature