ijms-20-00717-v2.pdf (2.54 MB)
Lipid–Protein Interactions in Niemann–Pick Type C Disease: Insights from Molecular Modeling
journal contributionposted 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.
CitationInternational Journal of Molecular Sciences, 2019, 20(3), 717;
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology
- VoR (Version of Record)