School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
Leicester Institute of Structural and Chemical Biology, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 7RH, UK.
Int J Mol Sci. 2019 Feb 7;20(3):717. doi: 10.3390/ijms20030717.
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.
尼曼-匹克 C 病（NPCD）细胞晚期内体和溶酶体中脂质的积累是一种蛋白质（通常是 NPC1）功能障碍的结果，但会导致许多蛋白质功能障碍。我们使用分子对接来提出：（a）NPC1 不仅可以输出胆固醇，还可以输出神经酰胺；（b）大钾通道（BK）的胆固醇敏感性可以追溯到通道电压传感器上一个以前未被重视的位点；（c）鞘磷脂对瞬时受体电位粘蛋白 1（TRPML1）的抑制作用可能是间接的；（d）磷脂酰肌醇负责膜联蛋白 A2（AnxA2）的定位错误和可溶性 NSF（N-乙基马来酰亚胺敏感融合蛋白）附着受体（SNARE）回收缺陷。这些结果是在 NPCD 的现有知识背景下提出的，以概述与该疾病相关的内溶酶体病理学的关键。
