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

Elghobashi-Meinhardt, Nadia

doi:10.3390/ijms21082962

Cited by 9 publications

(9 citation statements)

References 40 publications

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“…It is worth noting that modifying inter-domain interactions can modulate not only cholesterol transfer through a tunnel, but also by any other mechanism involving concerted domain interactions, such as a transfer of cholesterol to a different NPC1 molecule, or even a direct transfer to the membrane [86]. Limited movement of cholesterol along the putative tunnel was observed in a 100 ns simulation of NPC1 carrying the P691S mutation [87]. However, longer simulations with multiple replicas are required to confirm the statistical relevance of this observation.…”

Section: Plos Computational Biologymentioning

confidence: 97%

Cholesterol binding to the sterol-sensing region of Niemann Pick C1 protein confines dynamics of its N-terminal domain

et al. 2020

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Lysosomal accumulation of cholesterol is a hallmark of Niemann Pick type C (NPC) disease caused by mutations primarily in the lysosomal membrane protein NPC1. NPC1 contains a transmembrane sterol-sensing domain (SSD), which is supposed to regulate protein activity upon cholesterol binding, but the mechanisms underlying this process are poorly understood. Using atomistic simulations, we show that in the absence of cholesterol in the SSD, the luminal domains of NPC1 are highly dynamic, resulting in the disengagement of the NTD from the rest of the protein. The disengaged NPC1 adopts a flexed conformation that approaches the lipid bilayer, and could represent a conformational state primed to receive a sterol molecule from the soluble lysosomal cholesterol carrier NPC2. The binding of cholesterol to the SSD of NPC1 allosterically suppresses the conformational dynamics of the luminal domains resulting in an upright NTD conformation. The presence of an additional 20% cholesterol in the membrane has negligible impact on this process. The additional presence of an NTD-bound cholesterol suppresses the flexing of the NTD. We propose that cholesterol acts as an allosteric effector, and the modulation of NTD dynamics by the SSD-bound cholesterol constitutes an allosteric feedback mechanism in NPC1 that controls cholesterol abundance in the lysosomal membrane.

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Section: Plos Computational Biologymentioning

confidence: 97%

Cholesterol binding to the sterol-sensing region of Niemann Pick C1 protein confines dynamics of its N-terminal domain

et al. 2020

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“…The middle luminal domain (MLD) is also involved in the binding process. C-terminal domain (CTD) interacts with NTD to keep it in the proper orientation for receiving cholesterol during the export process ( Cologna and Rosenhouse-Dantsker, 2019 ; Elghobashi-Meinhardt, 2020 ). Three novel variants reported in this study are located in highly conserved regions related to CTD and MLD, indicating their potential roles in maintaining the NPC1 protein function.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Be Aware of “New” Features of Niemann–Pick Disease: Insights From Two Pediatric Cases

Chen

Guo

et al. 2022

Front. Genet.

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Niemann–Pick disease is a relatively common lysosomal storage disease. Cholestatic liver disease is a typical clinical phenotype of Niemann–Pick disease in infancy. The diagnosis is traditionally based on Niemann–Pick cells in bone marrow smears or liver biopsies. Treatment for cholestatic liver disease mainly includes ursodeoxycholic acid and liver protection drugs. Here, we reported two cases of Niemann–Pick disease type C, diagnosed by genetic analysis during early infancy. Besides cholestatic jaundice, the two patients also exhibited signs of immune system hyperactivity, such as elevated immunoglobulins or multiple autoantibodies, which might require the application of glucocorticoids. In addition, three novel missense variants of the NPC1 gene were identified. The findings suggest that immune activation should be considered as a “new” clinical phenotype of lysosomal storage diseases.

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“…In this context, the possible cholesterol binding sites have been recently suggested through the modeling study (Elghobashi‐Meinhardt, 2019). We note that the channel was observed in a short molecular dynamics simulation with no cholesterol in NTD (Elghobashi‐Meinhardt, 2020). Interestingly, the very recent molecular dynamics study of wild NPC1 with the cholesterol in itraconazole binding site indicates the migration of the cholesterol laterally toward the bilayer direction unlike the mutation P691S, which migrates away from SSD, suggesting that cholesterol might be inserted into bilayer, although this lateral motion for cholesterol transport out of the lysosome (Elghobashi‐Meinhardt, 2020).…”

Section: Introductionmentioning

confidence: 87%

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

Yoon

Jeong

Lee

et al. 2020

Journal of Neurochemistry

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The lysosomal membrane protein NPC1 (Niemann‐Pick type C1) and NPC2 (Niemann‐Pick type C2) 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 Niemann‐Pick disease type C (NPC) disease. The mutation R518W or R518Q on the NPC1 is one of 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 paper, 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 NTD (N‐terminal domain), toward the loop region in the MLD (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 NTD 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.

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

Cited by 9 publications

References 40 publications

Cholesterol binding to the sterol-sensing region of Niemann Pick C1 protein confines dynamics of its N-terminal domain

Cholesterol binding to the sterol-sensing region of Niemann Pick C1 protein confines dynamics of its N-terminal domain

Case Report: Be Aware of “New” Features of Niemann–Pick Disease: Insights From Two Pediatric Cases

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

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