5U74

Structure of human Niemann-Pick C1 protein

5U74 の概要

• エントリーDOI: 10.2210/pdb5u74/pdb
• 関連するPDBエントリー: 5U73
• 分子名称: Niemann-Pick C1 protein, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: npc1, membrane protein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Late endosome membrane ; Multi-pass membrane protein : O15118
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 145817.24

構造登録者

Li, X. (登録日: 2016-12-11, 公開日: 2017-10-11, 最終更新日: 2024-12-25)

主引用文献

Li, X.,Lu, F.,Trinh, M.N.,Schmiege, P.,Seemann, J.,Wang, J.,Blobel, G.
3.3 angstrom structure of Niemann-Pick C1 protein reveals insights into the function of the C-terminal luminal domain in cholesterol transport.
Proc. Natl. Acad. Sci. U.S.A., 114:9116-9121, 2017

PubMed Abstract: Niemann-Pick C1 (NPC1) and NPC2 proteins are indispensable for the export of LDL-derived cholesterol from late endosomes. Mutations in these proteins result in Niemann-Pick type C disease, a lysosomal storage disease. Despite recent reports of the NPC1 structure depicting its overall architecture, the function of its C-terminal luminal domain (CTD) remains poorly understood even though 45% of NPC disease-causing mutations are in this domain. Here, we report a crystal structure at 3.3 Å resolution of NPC1* (residues 314-1,278), which-in contrast to previous lower resolution structures-features the entire CTD well resolved. Notably, all eight cysteines of the CTD form four disulfide bonds, one of which (C909-C914) enforces a specific loop that in turn mediates an interaction with a loop of the N-terminal domain (NTD). Importantly, this loop and its interaction with the NTD were not observed in any previous structures due to the lower resolution. Our mutagenesis experiments highlight the physiological relevance of the CTD-NTD interaction, which might function to keep the NTD in the proper orientation for receiving cholesterol from NPC2. Additionally, this structure allows us to more precisely map all of the disease-causing mutations, allowing future molecular insights into the pathogenesis of NPC disease.

PubMed: 28784760
DOI: 10.1073/pnas.1711716114

実験手法

X-RAY DIFFRACTION (3.335 Å)