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


Authors: Gao, Y. G.; McDonald, J.; Malinina, L.; Patel, D. J.; Brown, R. E.
Article Title: Ceramide-1-phosphate transfer protein promotes sphingolipid reorientation needed for binding during membrane interaction
Abstract: 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. © 2021 THE AUTHORS.
Keywords: protein structure; lipid-transfer proteins; arabidopsis accelerated cell death (acd11) protein; ceramide-1- phosphate binding; gltp-fold alpha-helix induced lipid reorientation; human glycolipid transfer protein (gltp) superfamily; membranes/model; membranes/physical chemistry; peripheral membrane penetration depth
Journal Title: Journal of Lipid Research
Volume: 63
Issue: 1
ISSN: 0022-2275
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 2022-01-01
Start Page: 100151
Language: English
DOI: 10.1016/j.Jlr.2021.100151
PUBMED: 34808193
PROVIDER: scopus
PMCID: PMC8953657
DOI/URL:
Notes: Article -- Export Date: 1 February 2022 -- Source: Scopus
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  1. Dinshaw J Patel
    478 Patel