Molecular dynamics study with mutation shows that N‐terminal domain structural re‐orientation in Niemann‐Pick type C1 is required for proper alignment of cholesterol transport

• Published in: Journal of neurochemistry Vol. 156; no. 6; pp. 967 - 978
• Main Authors: Yoon, Hye‐Jin, Jeong, Hyunah, Lee, Hyung Ho, Jang, Soonmin
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2021; John Wiley and Sons Inc
• Subjects: Biological Transport; Brain diseases; Cholesterol; Cholesterol - metabolism; cholesterol trafficking; COVID‐19; Domains; Dynamic structural analysis; Endosomes - metabolism; Genetic disorders; Humans; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - genetics; Lipid Metabolism - genetics; Lipids; Lysosomes - metabolism; Membrane proteins; Metabolic disorders; Models, Molecular; Molecular dynamics; Molecular Dynamics Simulation; Mutation; Mutation - genetics; Neurodegenerative diseases; neurodegenerative Niemann‐Pick C disease; Niemann-Pick Disease, Type C - genetics; NPC1; Npc1 protein; NPC2; Original; ORIGINAL ARTICLES; Protein transport; Proteins; R518W mutant; Structure-function relationships; Vesicular Transport Proteins - chemistry; Vesicular Transport Proteins - genetics; X-Ray Diffraction; COVID-19; NPC1; NPC2; R518W mutant; cholesterol trafficking; molecular dynamics simulation; neurodegenerative Niemann-Pick C disease
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15150

The lysosomal membrane protein Niemann‐Pick type C1 (NPC1) and Niemann‐Pick type C2 (NPC2) are main players of cholesterol control in the lysosome and it is known that the mutation on these proteins leads to the cholesterol trafficking‐related neurodegenerative disease, which is called the NPC disease. The mutation R518W or R518Q on the NPC1 is one of the type of disease‐related mutation that causes cholesterol transports to be cut in half, which results in the accumulation of cholesterol and lipids in the late endosomal/lysosomal compartment of the cell. Even though there has been significant progress with understanding the cholesterol transport by NPC1 in combination with NPC2, especially after the structural determination of the full‐length NPC1 in 2016, many details such as the interaction of the full‐length NPC1 with the NPC2, the molecular motions responsible for the cholesterol transport during and after this interaction, and the structure and the function relations of many mutations are still not well understood. In this study, we report the extensive molecular dynamics simulations in order to gain insight into the structure and the dynamics of NPC1 lumenal domain for the cholesterol transport and the disease behind the mutation (R518W). It was found that the mutation induces a structural shift of the N‐terminal domain, toward the loop region in the middle lumenal domain, which is believed to play a central role in the interaction with NPC2 protein, so the interaction with the NPC2 protein might be less favorable compared to the wild NPC1. Also, the simulation indicates the possible re‐orientation of the N‐terminal domain with both the wild and the R518W‐mutated NPC1 after receiving the cholesterol from the NPC2 that align to form an internal tunnel, which is a possible pose for further action in cholesterol trafficking. We believe the current study can provide a better understanding of the cholesterol transport by NPC1 especially the role of NTD of NPC1 in combination with NPC2 interactions. We have performed a series of molecular dynamics simulation with lumenal domain Niemann‐Pick type C1 (NPC1) protein, which is one of the key protein that controls the cholesterol transport in lysosome, to investigate the dynamic role of N‐terminal domain (NTD). The simulation shows that the NTD makes proper orientation change for cholesterol trafficking depending on the environment. The same simulation with R518W‐mutated NPC1 shows possible reduced interaction between NPC1 and NPC2, which works in tandem with NPC1. The current modeling study provides insight into the structure and function relation of NPC1, including the disease causing R518W mutation in NPC1.