Identification and characterization of LPLAT7 as an sn-1-specific lysophospholipid acyltransferase

Kawana, Hiroki; Ozawa, Masaya; Shibata, Takeaki; Ohnishi, Hirofumi; Sato, Yukitaka; Kano, Kuniyuki; Shindou, Hideo; Shimizu, Takao; Kono, Nozomu; Aoki, Junken

doi:10.1016/j.jlr.2022.100271

Cited by 9 publications

(13 citation statements)

References 24 publications

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“…The amount of LysoPS in HEK293A cells and in supernatant from HEK293A cells stimulated by recombinant PS-PLA 1 was determined by LC-MS/MS analysis. Samples for LC-MS/MS analysis were prepared as described previously 49 . Briefly, HEK293A cells were stimulated by PS-PLA 1 as described above, and the entire supernatant was collected.…”

Section: Methodsmentioning

confidence: 99%

Structural basis for lysophosphatidylserine recognition by GPR34

Izume,

Kawahara,

Uwamizu

et al. 2024

Nat Commun

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GPR34 is a recently identified G-protein coupled receptor, which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative ligand. Here, we report cryo-electron microscopy structures of human GPR34-Gi complex bound with one of two ligands bound: either the LysoPS analogue S3E-LysoPS, or M1, a derivative of S3E-LysoPS in which oleic acid is substituted with a metabolically stable aromatic fatty acid surrogate. The ligand-binding pocket is laterally open toward the membrane, allowing lateral entry of lipidic agonists into the cavity. The amine and carboxylate groups of the serine moiety are recognized by the charged residue cluster. The acyl chain of S3E-LysoPS is bent and fits into the L-shaped hydrophobic pocket in TM4-5 gap, and the aromatic fatty acid surrogate of M1 fits more appropriately. Molecular dynamics simulations further account for the LysoPS-regioselectivity of GPR34. Thus, using a series of structural and physiological experiments, we provide evidence that chemically unstable 2-acyl LysoPS is the physiological ligand for GPR34. Overall, we anticipate the present structures will pave the way for development of novel anticancer drugs that specifically target GPR34.

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Section: Methodsmentioning

confidence: 99%

Structural basis for lysophosphatidylserine recognition by GPR34

Izume,

Kawahara,

Uwamizu

et al. 2024

Nat Commun

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“…The amount of LysoPS in HEK293A cells and in supernatant from HEK293A cells stimulated by recombinant PS-PLA 1 was determined by LC-MS/MS analysis. Samples for LC-MS/MS analysis were prepared as described previously 42 . Briefly, HEK293A cells were stimulated by PS-PLA 1 as described above, and the entire supernatant was collected.…”

Section: Methodsmentioning

confidence: 99%

“…LC-MS/MS analysis was performed as described previously 42 , using an LC-MS/MS system consisting of a Vanquish HPLC system and a TSQ Altis™ Triple-Stage Quadrupole Mass Spectrometer (Thermo Fisher Scientific). For HPLC, samples were separated in the L-column2 (100 mm×2 mm, 3-mm particle size, CERI), using a gradient solution consisting of solvent A (5 mM ammonium formate in water, pH 4.0) and solvent B (5 mM ammonium formate in acetonitrile, pH 4.0) at 200 ml/min.…”

Section: Lc-ms/ms Analysismentioning

confidence: 99%

Structural basis for lysophosphatidylserine recognition by GPR34

Izume

Kawahara

Uwamizu

et al. 2023

Preprint

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GPR34 is a recently identified G-protein coupled receptor, which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative ligand. Here, we report cryo-electron microscopy structures of human GPR34-Gi complex bound with either the LysoPS analogue S3E-LysoPS, which contains an ethoxy group at the sn-1 position, or M1, a derivative of S3E-LysoPS in which oleic acid is substituted with a metabolically stable aromatic fatty acid surrogate. In both structures, the ligand-binding pocket is laterally open toward the membrane, allowing lateral entry of lipidic agonists into the cavity. The amine and carboxylate groups of the serine moiety are recognized by the charged residue cluster, and the aromatic fatty acid surrogate of M1 forms stable hydrophobic interactions with the cavity, thus acting as a superagonist. Molecular dynamics simulations further account for the LysoPS-regioselectivity of GPR34. Thus, using a series of structural and physiological experiments, we provide evidence that chemically unstable 2-acyl LysoPS is the physiological ligand for GPR34, suggesting its short signal duration. Overall, we anticipate the present structures will pave the way for development of novel anticancer drugs that specifically target GPR34.

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“…For example, the reported enrichment in the PC 18 : 1/16 : 0 isomeric variant at the tips of neuronal cells has been attributed to acyl chain remodelling mediated by PLA 1 and alludes to unique biochemical functions of different sn ‐isomers [9] . In other studies changes in GPL sn‐ isomer populations have also been attributed to the s n ‐1 specificity of (i) of lysophosphatidylcholine acyltransferase‐1 (LPCAT1) where the activity of LPCAT1 could delineate cancerous and normal tissue regions of human hepatocellular carcinoma; [10] and (ii) lysophospholipid acyltransferase 7 (LPLAT7) [11] . These examples highlight the complex interplay between sn ‐isomers and various enzymatic‐driven metabolic processes.…”

Section: Figurementioning

confidence: 99%

“…[9] In other studies changes in GPL sn-isomer populations have also been attributed to the sn-1 specificity of (i) of lysophosphatidylcholine acyltransferase-1 (LPCAT1) where the activity of LPCAT1 could delineate cancerous and normal tissue regions of human hepatocellular carcinoma; [10] and (ii) lysophospholiipid acyltransferase 7 (LPLAT7). [11] These examples highlight the complex interplay between sn-isomers and various enzymatic-driven metabolic processes. Thus, techniques capable of characterising the sn-isomers of lipids are needed to enhance our fundamental biochemical understanding of lipid metabolism and its functions in a variety of diseases.…”

Section: Glycerophospholipidsmentioning

confidence: 99%

Deep Characterisation of the sn‐Isomer Lipidome Using High‐Throughput Data‐Independent Acquisition and Ozone‐Induced Dissociation**

Michael,

Young,

Balez

et al. 2024

Angew Chem Int Ed

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In recent years there has been a significant interest in the development of innovative lipidomics techniques capable of resolving lipid isomers. To date, methods applied to resolving sn‐isomers have resolved only a limited number of species. We report a workflow based on ozone‐induced dissociation for untargeted characterisation of hundreds of sn‐resolved glycerophospholipid isomers from biological extracts in under 20 minutes, coupled with an automated data analysis pipeline. It provides an order of magnitude increase over the number of sn‐isomer pairs identified compared to previous reports and reveals that sn‐isomer populations are tightly regulated and significantly different between cell lines. The sensitivity of this method and potential for de novo molecular discovery is further demonstrated by the identification of unexpected lipids containing ultra‐long chain monounsaturated acyl chains at the sn‐1 position.

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Identification and characterization of LPLAT7 as an sn-1-specific lysophospholipid acyltransferase

Cited by 9 publications

References 24 publications

Structural basis for lysophosphatidylserine recognition by GPR34

Structural basis for lysophosphatidylserine recognition by GPR34

Structural basis for lysophosphatidylserine recognition by GPR34

Deep Characterisation of the sn‐Isomer Lipidome Using High‐Throughput Data‐Independent Acquisition and Ozone‐Induced Dissociation**

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