3GKH

NPC1(NTD)

3GKH の概要

• エントリーDOI: 10.2210/pdb3gkh/pdb
• 関連するPDBエントリー: 3GKI 3GKJ
• 分子名称: Niemann-Pick C1 protein, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: cholesterol, cholesterol transfer, disease mutation, endosome, glycoprotein, lysosome, membrane, transmembrane, transport 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: 26568.74

構造登録者

Kwon, H.J. (登録日: 2009-03-10, 公開日: 2009-07-14, 最終更新日: 2024-10-16)

主引用文献

Kwon, H.J.,Abi-Mosleh, L.,Wang, M.L.,Deisenhofer, J.,Goldstein, J.L.,Brown, M.S.,Infante, R.E.
Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol.
Cell(Cambridge,Mass.), 137:1213-1224, 2009

PubMed Abstract: LDL delivers cholesterol to lysosomes by receptor-mediated endocytosis. Exit of cholesterol from lysosomes requires two proteins, membrane-bound Niemann-Pick C1 (NPC1) and soluble NPC2. NPC2 binds cholesterol with its isooctyl side chain buried and its 3beta-hydroxyl exposed. Here, we describe high-resolution structures of the N-terminal domain (NTD) of NPC1 and complexes with cholesterol and 25-hydroxycholesterol. NPC1(NTD) binds cholesterol in an orientation opposite to NPC2: 3beta-hydroxyl buried and isooctyl side chain exposed. Cholesterol transfer from NPC2 to NPC1(NTD) requires reorientation of a helical subdomain in NPC1(NTD), enlarging the opening for cholesterol entry. NPC1 with point mutations in this subdomain (distinct from the binding subdomain) cannot accept cholesterol from NPC2 and cannot restore cholesterol exit from lysosomes in NPC1-deficient cells. We propose a working model wherein after lysosomal hydrolysis of LDL-cholesteryl esters, cholesterol binds NPC2, which transfers it to NPC1(NTD), reversing its orientation and allowing insertion of its isooctyl side chain into the outer lysosomal membranes.

PubMed: 19563754
DOI: 10.1016/j.cell.2009.03.049

実験手法

X-RAY DIFFRACTION (1.81 Å)