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

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posted on 2019-09-10, 13:17 authored by Simon Wheeler, Ralf Schmid, Dan J. Sillence
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.

History

Citation

International Journal of Molecular Sciences, 2019, 20(3), 717;

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology

Version

  • VoR (Version of Record)

Published in

International Journal of Molecular Sciences

Publisher

MDPI

eissn

1422-0067

Acceptance date

2019-02-03

Copyright date

2019

Available date

2019-09-10

Publisher version

https://www.mdpi.com/1422-0067/20/3/717

Notes

Supplementary materials can be found at http://www.mdpi.com/1422-0067/20/3/717/s1.

Language

en

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