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

Date

2019-02-07

Advisors

Journal Title

Journal ISSN

ISSN

Volume Title

Publisher

MDPI

Type

Article

Peer reviewed

Yes

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.

Description

open access article

Keywords

Niemann-Pick, lipids, NPC1, BK, TRPML1, Annexin A2, SNARE

Citation

Wheeler, S. Schmid, R. and Sillence, D.J. (2019) Lipid–Protein Interactions in Niemann–Pick Type C Disease: Insights from Molecular Modeling. International Journal of Molecular Sciences, 20(3), pp.717.

Rights

Research Institute