9F41

Crystal structure of the NTD domain from S. cerevisia Niemann-Pick type C protein NCR1 with cholesterol bound

9F41 の概要

• エントリーDOI: 10.2210/pdb9f41/pdb
• 関連するPDBエントリー: 9F40
• 分子名称: NPC intracellular sterol transporter 1-related protein 1, ZINC ION, SULFATE ION, ... (14 entities in total)
• 機能のキーワード: cholesterol, vacuole, ncr1, membrane protein, niemann-pick type c protein
• 由来する生物種: Saccharomyces cerevisiae (brewer's yeast)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 127954.58

構造登録者

Nel, L.,Olesen, E.,Frain, K.M.,Pedersen, B.P. (登録日: 2024-04-26, 公開日: 2024-05-29, 最終更新日: 2024-11-06)

主引用文献

Nel, L.,Thaysen, K.,Jamecna, D.,Olesen, E.,Szomek, M.,Langer, J.,Frain, K.M.,Hoglinger, D.,Wustner, D.,Pedersen, B.P.
Structural and biochemical analysis of ligand binding in yeast Niemann-Pick type C1-related protein.
Life Sci Alliance, 8:-, 2025

PubMed Abstract: In eukaryotes, integration of sterols into the vacuolar/lysosomal membrane is critically dependent on the Niemann-Pick type C (NPC) system. The system consists of an integral membrane protein, called NCR1 in yeast, and NPC2, a luminal soluble protein that transfers sterols to the N-terminal domain (NTD) of NCR1 before membrane integration. Both proteins have been implicated in sterol homeostasis of yeast and humans. Here, we investigate sterol and lipid binding of the NCR1/NPC2 transport system and determine crystal structures of the sterol binding NTD. The NTD binds both ergosterol and cholesterol, with nearly identical conformations of the binding pocket. Apart from sterols, the NTD can also bind fluorescent analogs of phosphatidylinositol, phosphatidylcholine, and phosphatidylserine, as well as sphingosine and ceramide. We confirm the multi-lipid scope of the NCR1/NPC2 system using photo-crosslinkable and clickable lipid analogs, namely, pac-cholesterol, pac-sphingosine, and pac-ceramide. Finally, we reconstitute the transfer of pac-sphingosine from NPC2 to the NTD in vitro. Collectively, our results support that the yeast NPC system can work as versatile machinery for vacuolar homeostasis of structurally diverse lipids, besides ergosterol.

PubMed: 39455279
DOI: 10.26508/lsa.202402990

実験手法

X-RAY DIFFRACTION (2.64 Å)