Membrane curvature allosterically regulates the phosphatidylinositol cycle, controlling its rate and acyl-chain composition of its lipid intermediates

Bozelli, José Carlos; Jennings, William; Black, Stephanie; Hou, Y.; Lameire, Darius L.; Chatha, Preet; Kimura, Tomohiro; Berno, Bob; Khondker, Adree; Rheinstädter, Maikel C.; Epand, Richard M.

doi:10.1074/jbc.ra118.005293

Cited by 49 publications

(91 citation statements)

References 65 publications

(95 reference statements)

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“…Although our current findings support DGK C1 domains as a principal determinant of DAG fatty acyl specificity, future studies aimed at integrating C1 biology with additional regulatory mechanisms including, e.g. subcellular localization and membrane curvature 50 are needed to decipher DGK function in vivo .…”

Section: Discussionmentioning

confidence: 54%

Reprogramming fatty acyl specificity of lipid kinases via C1 domain engineering

et al. 2020

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C1 domains are lipid-binding modules that regulate membrane activation of kinases, nucleotide exchange factors, and other C1-containing proteins to trigger signal transduction. Despite annotation of typical C1 domains as diacylglycerol (DAG) and phorbol ester sensors, the function of atypical counterparts remains ill-defined. Here, we assign a key role for atypical C1 domains in mediating DAG fatty acyl specificity of diacylglycerol kinases (DGKs) in live cells. Activity-based proteomics mapped C1 probe binding as a principal differentiator of type 1 DGK active sites that combined with global metabolomics revealed a role for C1s in lipid substrate recognition. Protein engineering by C1 domain swapping demonstrated that exchange of typical and atypical C1s is functionally tolerated and can directly program DAG fatty acyl specificity of type 1 DGKs. Collectively, we describe a protein engineering strategy for studying metabolic specificity of lipid kinases to assign a role for atypical C1 domains in cell metabolism.

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Section: Discussionmentioning

confidence: 54%

Reprogramming fatty acyl specificity of lipid kinases via C1 domain engineering

et al. 2020

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“…However, upon membrane morphological changes (remodeling) DGKε showed enhanced specific activity and substrate acyl chain specificity. In particular, in the presence of membrane structures presenting negative Gaussian curvature SAG is DGKε preferred substrate . This type of curvature is observed on the structures reported to be produced by PLCβ1.…”

Section: Molecular Mechanisms Of Acyl Chain Specificitymentioning

confidence: 66%

“…However, the enzyme activity in vitro shows a high degree of acyl chain specificity for DAG containing 18:0/20:4 acyl chains (also known as 1‐stearoyl‐2‐arachidonoyl‐sn‐glycerol [SAG], which was suggested to be a consequence of an encoded conserved motif in the enzyme . Recently in vitro studies using purified DGKε and liposomes had shown that the substrate acyl chain specificity is not solely a consequence of the conserved motif in the enzyme but also due to the morphology of the membrane the enzyme binds to . It was shown that the activity and substrate acyl chain specificity of DGKε is positive allosterically regulated by membrane structures bearing a negative Gaussian curvature.…”

Section: Molecular Mechanisms Of Acyl Chain Specificitymentioning

confidence: 99%

“…DGKε catalyzes the next reaction within the PI cycle, that is, the ATP‐dependent phosphorylation of DAG to form PA. Recently, it has been shown that DGKε presents low specific activity and substrate acyl chain specificity in stable flat membranes . However, upon membrane morphological changes (remodeling) DGKε showed enhanced specific activity and substrate acyl chain specificity.…”

Section: Molecular Mechanisms Of Acyl Chain Specificitymentioning

confidence: 99%

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Specificity of Acyl Chain Composition of Phosphatidylinositols

Bozelli

Epand

2019

Proteomics

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Phosphatidylinositol (PI) lipids have a predominance of a single molecular species present through the organism. In healthy mammals this molecular species is 1‐stearoyl‐2‐arachidonoyl (18:0/20:4) PI. Although the importance of PI lipids for cell physiology has long been appreciated, less is known about the biological role of enriching PI lipids with 18:0/20:4 acyl chains. In conditions with dysfunctional lipid metabolism, the predominance of 18:0/20:4 acyl chains is lost. Recently, molecular mechanisms underpinning the enrichment or alteration of these acyl chains in PI lipids have begun to emerge. In the majority of the cases a common feature is the presence of enzymes bearing substrate acyl chain specificity. However, in cancer cells, it has been shown that one (not the only) of the mechanisms responsible for the loss in this acyl chain enrichment is mutation on the transcription factor p53 gene, which is one of the most highly mutated genes in cancers. There is a compelling need for a global picture of the specificity of the acyl chain composition of PIs. This can be possible once high‐resolution spatio‐temporal information is gathered in a cellular context; which can ultimately lead to potential novel targets to combat conditions with altered PI acyl chain profiles.

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“…In addition, myristoyl and palmitoyl moieties favor L o lipid structures while isoprenyl moieties favor L d lipid structures [29]. Non-lamellar-prone lipids also regulate the membrane shape, and negative Gaussian curvature enhances the activity of DGKe and controls the PtdIns-cycle at endoplasmic reticulum-plasma membrane contact sites [92,93]. Given the relevance of PtdIns in cellular functions, the membrane shape appears to be a critical parameter in the cell's physiology.…”

Section: How Membrane Lipid Structure Influences Protein-lipid Interamentioning

confidence: 99%

The Implications for Cells of the Lipid Switches Driven by Protein–Membrane Interactions and the Development of Membrane Lipid Therapy

Torres

Rosselló

Fernández‐García

et al. 2020

IJMS

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The cell membrane contains a variety of receptors that interact with signaling molecules. However, agonist–receptor interactions not always activate a signaling cascade. Amphitropic membrane proteins are required for signal propagation upon ligand-induced receptor activation. These proteins localize to the plasma membrane or internal compartments; however, they are only activated by ligand-receptor complexes when both come into physical contact in membranes. These interactions enable signal propagation. Thus, signals may not propagate into the cell if peripheral proteins do not co-localize with receptors even in the presence of messengers. As the translocation of an amphitropic protein greatly depends on the membrane’s lipid composition, regulation of the lipid bilayer emerges as a novel therapeutic strategy. Some of the signals controlled by proteins non-permanently bound to membranes produce dramatic changes in the cell’s physiology. Indeed, changes in membrane lipids induce translocation of dozens of peripheral signaling proteins from or to the plasma membrane, which controls how cells behave. We called these changes “lipid switches”, as they alter the cell’s status (e.g., proliferation, differentiation, death, etc.) in response to the modulation of membrane lipids. Indeed, this discovery enables therapeutic interventions that modify the bilayer’s lipids, an approach known as membrane-lipid therapy (MLT) or melitherapy.

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Membrane curvature allosterically regulates the phosphatidylinositol cycle, controlling its rate and acyl-chain composition of its lipid intermediates

Cited by 49 publications

References 65 publications

Reprogramming fatty acyl specificity of lipid kinases via C1 domain engineering

Reprogramming fatty acyl specificity of lipid kinases via C1 domain engineering

Specificity of Acyl Chain Composition of Phosphatidylinositols

The Implications for Cells of the Lipid Switches Driven by Protein–Membrane Interactions and the Development of Membrane Lipid Therapy

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