Phosphatidylinositol phosphates modulate interactions between the StarD4 sterol trafficking protein and lipid membranes

Zhang, Xiaoxue; Xie, Hengyi; Iaea, David B.; Khelashvili, George; Weinstein, Harel; Maxfield, Frederick R.

doi:10.1016/j.jbc.2022.102058

Cited by 17 publications

(55 citation statements)

References 63 publications

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“…Because the catalytic mechanism described here is closely related to that of passive lipid transport [ 25 , 26 ], we suspect this biophysical mechanism may be generally used by lipid transfer proteins, not just CPTP, to increase the rate of lipid transport between cell membranes. For example, the sterol transfer protein StarD4 has been shown to deform donor membranes [ 57 ], as one would expect for a protein that catalyzes lipid extraction by disrupting a lipid’s local hydrophobic environment [ 26 ]. Nevertheless, we expect the precise molecular details to vary from protein to protein.…”

Section: Discussionmentioning

confidence: 99%

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

Rogers

Geissler

2023

PLoS Comput Biol

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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 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 significantly 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. Insertion of C1P into an acceptor membrane, eased by a decrease in membrane order by CPTP, restarts the transfer cycle. Most notably, we provide molecular evidence for CPTP’s ability to catalyze C1P extraction by breaking hydrophobic C1P–membrane contacts with compensatory hydrophobic lipid–protein contacts. Our work, thus, provides biophysical insights into how CPTP efficiently traffics C1P between membranes to maintain sphingolipid homeostasis and, additionally, presents a simulation method aptly suited for uncovering the catalytic mechanisms of other lipid transfer proteins.

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Section: Discussionmentioning

confidence: 99%

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

Rogers

Geissler

2023

PLoS Comput Biol

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“…Because the catalytic mechanism described here is closely related to that of passive lipid transport [25, 26], we suspect it may be generally used by lipid transfer proteins, not just CPTP, to increase the rate of lipid transport between cell membranes. For example, the sterol transfer protein StarD4 has been shown to deform donor membranes [48], as one would expect for a protein that catalyzes lipid transfer by disrupting a lipid’s local hydrophobic environment [26]. Our mulitscale simulation approach provides a framework to efficiently test this hypothesis and, thus, advance our understanding of how lipid transfer proteins rapidly traffic lipids to ensure membrane homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Contact pairs used to calculate Q include: (1) pairs of hydrophobic carbons of C1P and carbons of the residues that line CPTP's hydrophobic cavity (residues10,14,36,39,40,42,43,46,48,50,52,53,57, 110, 111, 114, 117, 118, 121, 122, 146, 150, 153, 154, 158, 162, 165, 171, and 175) that have ⟨r ij ⟩ ≤ 7.8 Å during solution-phase simulations of the C1P-bound form of CPTP; and (2) pairs of heavy atoms of C1P's headgroup and sphingoid backbone and heavy atoms of the residues responsible for C1P recognition (residues 52, 53, 56, 60, 96−102, 106, 110, 113, 114, 146−151, 154, and 214) that have have ⟨r ij ⟩ ≤ 5.5 Å during solution-phase simulations of the C1P-bound form.…”

mentioning

confidence: 99%

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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“…Tethering MIGA2 to the liposomes assures that the protein interacts with the liposome, providing an opportunity for it to capture/extract lipid substrate, a stochastic event that determines the rate of the lipid transfer reaction. In the absence of a tether, whether a protein stays associated with membrane long enough for efficient lipid extraction depends heavily on the donor membrane composition (for example, see Horenkamp et al, 2018 ; Zhang et al, 2022 ); often the presence of acidic lipid ( Kim et al [2022] used 10% NBD-PS, much more than would be present in ER, mitochondria, or LDs) enhances protein interaction with membranes. We suspect that the transfer rates they observed reflect differences in lipid extraction rates arising from different donor liposome compositions and membrane characteristics, and that transfer of NBD-PC, -PA, and -PE would be enhanced upon addition of unlabeled PS to the donor liposomes.…”

Section: Resultsmentioning

confidence: 99%

Mitoguardin-2–mediated lipid transfer preserves mitochondrial morphology and lipid droplet formation

Hong

Adlakha

Wan

et al. 2022

Journal of Cell Biology

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Lipid transport proteins at membrane contacts, where organelles are closely apposed, are critical in redistributing lipids from the endoplasmic reticulum (ER), where they are made, to other cellular membranes. Such protein-mediated transfer is especially important for maintaining organelles disconnected from secretory pathways, like mitochondria. We identify mitoguardin-2, a mitochondrial protein at contacts with the ER and/or lipid droplets (LDs), as a lipid transporter. An x-ray structure shows that the C-terminal domain of mitoguardin-2 has a hydrophobic cavity that binds lipids. Mass spectrometry analysis reveals that both glycerophospholipids and free-fatty acids co-purify with mitoguardin-2 from cells, and that each mitoguardin-2 can accommodate up to two lipids. Mitoguardin-2 transfers glycerophospholipids between membranes in vitro, and this transport ability is required for roles both in mitochondrial and LD biology. While it is not established that protein-mediated transfer at contacts plays a role in LD metabolism, our findings raise the possibility that mitoguardin-2 functions in transporting fatty acids and glycerophospholipids at mitochondria-LD contacts.

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Phosphatidylinositol phosphates modulate interactions between the StarD4 sterol trafficking protein and lipid membranes

Cited by 17 publications

References 63 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

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

Mitoguardin-2–mediated lipid transfer preserves mitochondrial morphology and lipid droplet formation

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