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Title: Lipid–Protein Interactions in Niemann–Pick Type C Disease: Insights from Molecular Modeling
Authors: Wheeler, Simon
Schmid, Ralf
Sillence, Dan J.
First Published: 7-Feb-2019
Publisher: MDPI
Citation: International Journal of Molecular Sciences, 2019, 20(3), 717;
Abstract: 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.
DOI Link: 10.3390/ijms20030717
eISSN: 1422-0067
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2019. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description: Supplementary materials can be found at
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

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