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Molecular Pathways and Respiratory Involvement in Lysosomal Storage Diseases
Open AccessArticle

Lipid–Protein Interactions in Niemann–Pick Type C Disease: Insights from Molecular Modeling

1
School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK
2
Leicester Institute of Structural and Chemical Biology, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 7RH, UK
3
Department of Molecular and Cell Biology, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 7RH, UK
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(3), 717; https://doi.org/10.3390/ijms20030717
Received: 16 January 2019 / Revised: 31 January 2019 / Accepted: 3 February 2019 / Published: 7 February 2019
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
The accumulation of lipids in the late endosomes and lysosomes of Niemann–Pick type C disease (NPCD) cells is a consequence of the dysfunction of one protein (usually NPC1) but induces dysfunction in many proteins. We used molecular docking to propose (a) that NPC1 exports not just cholesterol, but also sphingosine, (b) that the cholesterol sensitivity of big potassium channel (BK) can be traced to a previously unappreciated site on the channel’s voltage sensor, (c) that transient receptor potential mucolipin 1 (TRPML1) inhibition by sphingomyelin is likely an indirect effect, and (d) that phosphoinositides are responsible for both the mislocalization of annexin A2 (AnxA2) and a soluble NSF (N-ethylmaleimide Sensitive Fusion) protein attachment receptor (SNARE) recycling defect. These results are set in the context of existing knowledge of NPCD to sketch an account of the endolysosomal pathology key to this disease. View Full-Text
Keywords: Niemann–Pick; lipids; NPC1; BK; TRPML1; Annexin A2; SNARE Niemann–Pick; lipids; NPC1; BK; TRPML1; Annexin A2; SNARE
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Wheeler, S.; Schmid, R.; Sillence, D.J. Lipid–Protein Interactions in Niemann–Pick Type C Disease: Insights from Molecular Modeling. Int. J. Mol. Sci. 2019, 20, 717.

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