Ceramide-1-phosphate transfer protein promotes sphingolipid reorientation needed for binding during membrane interaction

Yong Guang Gao, Jeffrey McDonald, Lucy Malinina, Dinshaw J. Patel, Rhoderick E. Brown

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Lipid transfer proteins acquire and release their lipid cargoes by interacting transiently with source and destination biomembranes. In the Glyco-Lipid Transfer Protein (GLTP) superfamily, the twolayer all-α-helical GLTP-fold defines proteins that specifically target sphingolipids (SLs) containing either sugar or phosphate headgroups via their conserved but evolutionarily-modified SL recognitions centers. Despite comprehensive structural insights provided by X-ray crystallography, the conformational dynamics associated with membrane interaction and SL uptake/release by GLTP superfamily members have remained unknown. Herein, we report insights gained from molecular dynamics (MD) simulations into the conformational dynamics that enable ceramide-1-phosphate transfer proteins (CPTPs) to acquire and deliver ceramide-1-phosphate (C1P) during interaction with 1-palmitoyl-2-oleoyl phosphatidylcholine bilayers. The focus on CPTP reflects this protein's involvement in regulating proinflammatory eicosanoid production and autophagydependent inflammasome assembly that drives interleukin (IL-1β and IL-18) production and release by surveillance cells. We found that membrane penetration by CPTP involved α-6 helix and the α-2 helix N-terminal region, was confined to one bilayer leaflet, and was relatively shallow. Large-scale dynamic conformational changes were minimal for CPTP during membrane interaction or C1P uptake except for the α-3/α-4 helices connecting loop, which is located near the membrane interface and interacts with certain phosphoinositide headgroups. Apart from functioning as a shallow membrane-docking element, α-6 helix was found to adeptly reorient membrane lipids to help guide C1P hydrocarbon chain insertion into the interior hydrophobic pocket of the SL binding site. These findings support a proposed 'hydrocarbon chain-first' mechanism for C1P uptake, in contrast to the 'lipid polar headgroup-first' uptake used by most lipid-transfer proteins.

Original languageEnglish (US)
Article number100151
JournalJournal of lipid research
Issue number1
StatePublished - Jan 1 2022

Bibliographical note

Publisher Copyright:


  • Arabidopsis accelerated cell death (ACD11) protein
  • Ceramide-1- phosphate binding
  • GLTP-fold alpha-helix induced lipid reorientation
  • Human glycolipid transfer protein (GLTP) superfamily
  • Lipid-transfer proteins
  • Membranes/model
  • Membranes/physical chemistry
  • Peripheral membrane penetration depth
  • Protein structure


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