4K8N

Crystal structure of human ceramide-1-phosphate transfer protein (CPTP) in complex with 18:1 Ceramide-1-Phosphate (18:1-C1P)

4K8N の概要

• エントリーDOI: 10.2210/pdb4k8n/pdb
• 関連するPDBエントリー: 4K80 4K84 4K85 4KBR 4KBS 4KF6
• 分子名称: Glycolipid transfer protein domain-containing protein 1, (2S,3R,4Z)-3-hydroxy-2-[(9E)-octadec-9-enoylamino]octadec-4-en-1-yl dihydrogen phosphate (3 entities in total)
• 機能のキーワード: lipid transfer protein, gltp-fold, cptp, c1p, ceramide-1-phosphate, protein-lipid complex, eicosanoid, lipid transport
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 150768.43

構造登録者

Simanshu, D.K.,Brown, R.E.,Patel, D.J. (登録日: 2013-04-18, 公開日: 2013-07-17, 最終更新日: 2024-10-30)

主引用文献

Simanshu, D.K.,Kamlekar, R.K.,Wijesinghe, D.S.,Zou, X.,Zhai, X.,Mishra, S.K.,Molotkovsky, J.G.,Malinina, L.,Hinchcliffe, E.H.,Chalfant, C.E.,Brown, R.E.,Patel, D.J.
Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids.
Nature, 500:463-467, 2013

PubMed Abstract: Phosphorylated sphingolipids ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P) have emerged as key regulators of cell growth, survival, migration and inflammation. C1P produced by ceramide kinase is an activator of group IVA cytosolic phospholipase A2α (cPLA2α), the rate-limiting releaser of arachidonic acid used for pro-inflammatory eicosanoid production, which contributes to disease pathogenesis in asthma or airway hyper-responsiveness, cancer, atherosclerosis and thrombosis. To modulate eicosanoid action and avoid the damaging effects of chronic inflammation, cells require efficient targeting, trafficking and presentation of C1P to specific cellular sites. Vesicular trafficking is likely but non-vesicular mechanisms for C1P sensing, transfer and presentation remain unexplored. Moreover, the molecular basis for selective recognition and binding among signalling lipids with phosphate headgroups, namely C1P, phosphatidic acid or their lyso-derivatives, remains unclear. Here, a ubiquitously expressed lipid transfer protein, human GLTPD1, named here CPTP, is shown to specifically transfer C1P between membranes. Crystal structures establish C1P binding through a novel surface-localized, phosphate headgroup recognition centre connected to an interior hydrophobic pocket that adaptively expands to ensheath differing-length lipid chains using a cleft-like gating mechanism. The two-layer, α-helically-dominated 'sandwich' topology identifies CPTP as the prototype for a new glycolipid transfer protein fold subfamily. CPTP resides in the cell cytosol but associates with the trans-Golgi network, nucleus and plasma membrane. RNA interference-induced CPTP depletion elevates C1P steady-state levels and alters Golgi cisternae stack morphology. The resulting C1P decrease in plasma membranes and increase in the Golgi complex stimulates cPLA2α release of arachidonic acid, triggering pro-inflammatory eicosanoid generation.

PubMed: 23863933
DOI: 10.1038/nature12332

実験手法

X-RAY DIFFRACTION (3.102 Å)