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

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

doi:10.1016/j.jlr.2021.100151

Cited by 6 publications

(23 citation statements)

References 78 publications

(205 reference statements)

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“…In both apo and C1P-bound forms, the loop connecting helices α1 and α2 along with helix α6 inserts into the membrane's hydrophobic core (Fig 2A). A combination of hydrophobic and aromatic residues, specifically I49, F50, and F52 of the α1-α2 loop and W152, V153, and V160 of helix α6, anchor CPTP to the membrane as predicted from crystal structures [16] and identified in previous simulations [27]. When bound to the membrane, the entrance to CPTP's hydrophobic cavity is aptly positioned at the membrane-solvent interface (Fig 2B and 2C).…”

Section: Membrane Binding Poises Cptp To Extract C1pmentioning

confidence: 55%

“…which has previously been shown to be stable in all-atom MD simulations [27]. In both apo and C1P-bound forms, the loop connecting helices α1 and α2 along with helix α6 inserts into the membrane's hydrophobic core (Fig 2A).…”

Section: Membrane Binding Poises Cptp To Extract C1pmentioning

confidence: 80%

“…Including PS, PI(4,5)P 2 , or PI4P, but not other anionic lipids, in donor membranes has been shown to enhance C1P transport in in vitro assays [19, 20]. Through specific interactions with CPTP’s helix α 6 and α 3 – α 4 loop, these lipids may help position the entrance to CPTP’s hydrophobic cavity at the membrane surface and regulate its activity [19, 20, 27]. We hypothesize that PS, PI(4,5)P 2 , and PI4P may also interact with arginine and lysine residues on helix α 2 when CPTP is bound to the membrane in its apo form.…”

Section: Discussionmentioning

confidence: 99%

“…When bound to the membrane, CPTP also influences the molecular structure and physical properties of the membrane. Previous simulations suggested that helix α6, in particular, can promote lipid reorientation into configurations apt for tail-first uptake by CPTP: By orienting lipids parallel with the membrane surface, the terminal carbons of their hydrophobic tails are positioned at the membrane surface and pointing into CPTP's hydrophobic cavity [27]. Consistent with this idea, we find that the hydrophobic tails of lipids in close proximity to both the apo and C1P-bound forms of CPTP are oriented more parallel to the membrane surface than expected for a POPC membrane without CPTP bound (Fig 5 A coordinate system is defined by the plane containing helix α6, which nearly corresponds to the location of the membrane-solvent interface when CPTP is membrane bound.…”

Section: Cptp Alters the Membrane's Physical Properties To Facilitate...mentioning

confidence: 99%

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Ceramide-1-phosphate transfer protein enhances lipid transport by disrupting hydrophobic lipid–membrane contacts

Rogers

Geissler

2022

Preprint

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Cellular distributions of the sphingolipid ceramide-1-phosphate (C1P) impact essential biological processes. C1P levels are spatiotemporally regulated by ceramide-1-phosphate transfer protein (CPTP), which efficiently shuttles C1P between organelle membranes. Yet, how CPTP rapidly extracts and inserts C1P into a membrane remains unknown. Here, we devise a multiscale simulation approach to elucidate the biophysical details of CPTP-mediated C1P transport. We find that CPTP binds a membrane poised to extract and insert C1P and that membrane binding promotes conformational changes in CPTP that facilitate C1P uptake and release. By substantially disrupting a lipid's local hydrophobic environment in the membrane, CPTP lowers the activation free energy barrier for passive C1P desorption and enhances C1P extraction from the membrane. Upon uptake of C1P, further conformational changes may aid membrane unbinding in a manner reminiscent of the electrostatic switching mechanism used by other lipid transfer proteins. Most notably, we provide molecular evidence for CPTP's ability to catalyze C1P transport by breaking hydrophobic C1P–membrane contacts. Since this catalytic mechanism is biophysically related to that of passive lipid transport, it may be ubiquitously used by lipid transport proteins to rapidly traffic lipids between membranes and ensure membrane homeostasis.

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Section: Membrane Binding Poises Cptp To Extract C1pmentioning

confidence: 55%

Section: Membrane Binding Poises Cptp To Extract C1pmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Cptp Alters the Membrane's Physical Properties To Facilitate...mentioning

confidence: 99%

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Ceramide-1-phosphate transfer protein enhances lipid transport by disrupting hydrophobic lipid–membrane contacts

Rogers

Geissler

2022

Preprint

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“…Like Ta DIR1‐2 and At LTP3, Accelerated Cell Death 11 (ACD11) in Arabidopsis also has a negative effect on plant immunity (Brodersen et al, 2002). ACD11 encodes an LTP and is able to transfer ceramide‐1‐phosphate (C1P), which plays important roles in plant growth, development, senescence and programmed cell death (PCD) (Gao et al, 2022; Simanshu et al, 2014; Zhai et al, 2017). X‐ray structures showed that ACD11 belongs to the glycolipid transfer protein superfamily.…”

Section: Role Of Ltp In Negative Regulation Of Plant Immune Responsesmentioning

confidence: 99%

Lipid transfer proteins involved in plant–pathogen interactions and their molecular mechanisms

Gao

et al. 2022

Molecular Plant Pathology

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Nonspecific lipid transfer proteins (LTPs) were first isolated from potato tubers and identified by Kader (1975). LTPs are ubiquitous small proteins (molecular weights ranging from 6.5 to 10 kDa) that exist in all terrestrial plants (Salminen et al., 2016). They have eight cysteine residue motifs that form four conserved disulphide bridges, which help stabilize the peptide tertiary structure, and many α-helices with a central hydrophobic cavity capable of binding to a variety of lipids such as fatty acids, fatty acyl-CoA, phospholipids, and prostaglandin B2 (Madni et al., 2020;Salminen et al., 2016). LTPs are encoded by large gene families and expressed abundantly in a variety of plant tissues. Almost all nonspecific LTPs carry an N-terminal signal that localizes the protein at the subcellular level (Edstam et al., 2011;Missaoui et al., 2022). Traditionally, LTPs are classified according to molecular weight or sequence identity (Boutrot et al., 2008;Kalla et al., 1994). A more recent classification system by Edstam et al. (2011) uses five major types (LTP1, LTP2, LTPc, LTPd and LTPg) and five minor types (LTPe, LTPf, LTPh, LTPj and LTPk) based on the position of a conserved intron, the amino acid sequence identity, and posttranslational modifications. Expression of many nonspecific LTPs can be induced by multiple biotic and abiotic stresses, including

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Membrane specificity of the human cholesterol transfer protein STARD4

Talandashti,

van Ek,

Gehin

et al. 2024

Journal of Molecular Biology

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

Cited by 6 publications

References 78 publications

Ceramide-1-phosphate transfer protein enhances lipid transport by disrupting hydrophobic lipid–membrane contacts

Ceramide-1-phosphate transfer protein enhances lipid transport by disrupting hydrophobic lipid–membrane contacts

Lipid transfer proteins involved in plant–pathogen interactions and their molecular mechanisms

Membrane specificity of the human cholesterol transfer protein STARD4

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