Ceramide-1-phosphate transfer protein promotes sphingolipid reorientation needed for binding during membrane interaction
| Autor: | Yong-Guang Gao, Rhoderick E. Brown, Lucy Malinina, Dinshaw J. Patel, Jeffrey G. McDonald |
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| Rok vydání: | 2021 |
| Předmět: |
biology
Chemistry Membrane lipids Cell Biology Arabidopsis accelerated cell death (ACD11) protein QD415-436 Sphingolipid Biochemistry Pleckstrin homology domain Endocrinology Protein structure lipid-transfer proteins Glycolipid transfer protein Helix biology.protein Biophysics membranes/model lipids (amino acids peptides and proteins) Ceramide 1-phosphate binding protein structure Phospholipid Transfer Proteins membranes/physical chemistry human glycolipid transfer protein (GLTP) superfamily Plant lipid transfer proteins |
| Zdroj: | Journal of Lipid Research, Vol 63, Iss 1, Pp 100151-(2022) |
| ISSN: | 1539-7262 |
| Popis: | Lipid transfer proteins acquire and release their lipid cargoes by interacting transiently with source and destination biomembranes. In the GlycoLipid Transfer Protein (GLTP) superfamily, the two-layer 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 pro-inflammatory eicosanoid production and autophagy-dependent 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. |
| Databáze: | OpenAIRE |
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