| Structural highlights
Function
LRAT_MOUSE Transfers the acyl group from the sn-1 position of phosphatidylcholine to all-trans retinol, producing all-trans retinyl esters. Retinyl esters are storage forms of vitamin A (PubMed:28758396). LRAT plays a critical role in vision (By similarity). It provides the all-trans retinyl ester substrates for the isomerohydrolase which processes the esters into 11-cis-retinol in the retinal pigment epithelium; due to a membrane-associated alcohol dehydrogenase, 11 cis-retinol is oxidized and converted into 11-cis-retinaldehyde which is the chromophore for rhodopsin and the cone photopigments (By similarity). Required for the survival of cone photoreceptors and correct rod photoreceptor cell morphology (PubMed:25416279).[UniProtKB:O95237][1] [2] PLAT3_HUMAN Exhibits both phospholipase A1/2 and acyltransferase activities (PubMed:19615464, PubMed:19047760, PubMed:22825852, PubMed:22605381, PubMed:26503625). Shows phospholipase A1 (PLA1) and A2 (PLA2) activity, catalyzing the calcium-independent release of fatty acids from the sn-1 or sn-2 position of glycerophospholipids (PubMed:19615464, PubMed:19047760, PubMed:22825852, PubMed:22605381, PubMed:22923616). For most substrates, PLA1 activity is much higher than PLA2 activity (PubMed:19615464). Shows O-acyltransferase activity,catalyzing the transfer of a fatty acyl group from glycerophospholipid to the hydroxyl group of lysophospholipid (PubMed:19615464). Shows N-acyltransferase activity, catalyzing the calcium-independent transfer of a fatty acyl group at the sn-1 position of phosphatidylcholine (PC) and other glycerophospholipids to the primary amine of phosphatidylethanolamine (PE), forming N-acylphosphatidylethanolamine (NAPE), which serves as precursor for N-acylethanolamines (NAEs) (PubMed:19615464, PubMed:19047760, PubMed:22825852, PubMed:22605381). Exhibits high N-acyltransferase activity and low phospholipase A1/2 activity (PubMed:22825852). Required for complete organelle rupture and degradation that occur during eye lens terminal differentiation, when fiber cells that compose the lens degrade all membrane-bound organelles in order to provide lens with transparency to allow the passage of light. Organelle membrane degradation is probably catalyzed by the phospholipase activity (By similarity).[UniProtKB:Q8R3U1][3] [4] [5] [6] [7] [8] (Microbial infection) Acts as a host factor for picornaviruses: required during early infection to promote viral genome release into the cytoplasm (PubMed:28077878). May act as a cellular sensor of membrane damage at sites of virus entry, which relocalizes to sites of membrane rupture upon virus unfection (PubMed:28077878). Facilitates safe passage of the RNA away from LGALS8, enabling viral genome translation by host ribosome (PubMed:28077878). May also be involved in initiating pore formation, increasing pore size or in maintaining pores for genome delivery (PubMed:28077878). The lipid-modifying enzyme activity is required for this process (PubMed:28077878).[9]
Publication Abstract from PubMed
Cellular uptake of vitamin A, production of visual chromophore and triglyceride homeostasis in adipocytes depend on two representatives of the vertebrate N1pC/P60 protein family, lecithin:retinol acyltransferase (LRAT) and HRAS-like tumor suppressor 3 (HRASLS3). Both proteins function as lipid-metabolizing enzymes but differ in their substrate preferences and dominant catalytic activity. The mechanism of this catalytic diversity is not understood. Here, by using a gain-of-function approach, we identified a specific sequence responsible for the substrate specificity of N1pC/P60 proteins. A 2.2-A crystal structure of the HRASLS3-LRAT chimeric enzyme in a thioester catalytic intermediate state revealed a major structural rearrangement accompanied by three-dimensional domain swapping dimerization not observed in native HRASLS proteins. Structural changes affecting the active site environment contributed to slower hydrolysis of the catalytic intermediate, supporting efficient acyl transfer. These findings reveal structural adaptation that facilitates selective catalysis and mechanism responsible for diverse substrate specificity within the LRAT-like enzyme family.
LRAT-specific domain facilitates vitamin A metabolism by domain swapping in HRASLS3.,Golczak M, Sears AE, Kiser PD, Palczewski K Nat Chem Biol. 2015 Jan;11(1):26-32. doi: 10.1038/nchembio.1687. Epub 2014 Nov, 10. PMID:25383759[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhang T, Enemchukwu NO, Jones A, Wang S, Dennis E, Watt CB, Pugh EN Jr, Fu Y. Genetic deletion of S-opsin prevents rapid cone degeneration in a mouse model of Leber congenital amaurosis. Hum Mol Genet. 2015 Mar 15;24(6):1755-63. PMID:25416279 doi:10.1093/hmg/ddu588
- ↑ Chelstowska S, Widjaja-Adhi MAK, Silvaroli JA, Golczak M. Impact of LCA-Associated E14L LRAT Mutation on Protein Stability and Retinoid Homeostasis. Biochemistry. 2017 Aug 29;56(34):4489-4499. PMID:28758396 doi:10.1021/acs.biochem.7b00451
- ↑ Uyama T, Morishita J, Jin XH, Okamoto Y, Tsuboi K, Ueda N. The tumor suppressor gene H-Rev107 functions as a novel Ca2+-independent cytosolic phospholipase A1/2 of the thiol hydrolase type. J Lipid Res. 2009 Apr;50(4):685-93. doi: 10.1194/jlr.M800453-JLR200. Epub 2008, Dec 1. PMID:19047760 doi:http://dx.doi.org/10.1194/jlr.M800453-JLR200
- ↑ Uyama T, Jin XH, Tsuboi K, Tonai T, Ueda N. Characterization of the human tumor suppressors TIG3 and HRASLS2 as phospholipid-metabolizing enzymes. Biochim Biophys Acta. 2009 Dec;1791(12):1114-24. doi:, 10.1016/j.bbalip.2009.07.001. Epub 2009 Jul 14. PMID:19615464 doi:http://dx.doi.org/10.1016/j.bbalip.2009.07.001
- ↑ Golczak M, Kiser PD, Sears AE, Lodowski DT, Blaner WS, Palczewski K. Structural Basis for the Acyltransferase Activity of Lecithin:Retinol Acyltransferase-like Proteins. J Biol Chem. 2012 Jul 6;287(28):23790-807. Epub 2012 May 17. PMID:22605381 doi:10.1074/jbc.M112.361550
- ↑ Uyama T, Ikematsu N, Inoue M, Shinohara N, Jin XH, Tsuboi K, Tonai T, Tokumura A, Ueda N. Generation of N-acylphosphatidylethanolamine by members of the phospholipase A/acyltransferase (PLA/AT) family. J Biol Chem. 2012 Sep 14;287(38):31905-19. doi: 10.1074/jbc.M112.368712. Epub, 2012 Jul 23. PMID:22825852 doi:http://dx.doi.org/10.1074/jbc.M112.368712
- ↑ Pang XY, Cao J, Addington L, Lovell S, Battaile KP, Zhang N, Rao JL, Dennis EA, Moise AR. Structure/Function Relationships of Adipose Phospholipase A2 Containing a Cys-His-His Catalytic Triad. J Biol Chem. 2012 Aug 25. PMID:22923616 doi:http://dx.doi.org/10.1074/jbc.M112.398859
- ↑ Mardian EB, Bradley RM, Duncan RE. The HRASLS (PLA/AT) subfamily of enzymes. J Biomed Sci. 2015 Oct 26;22:99. doi: 10.1186/s12929-015-0210-7. PMID:26503625 doi:http://dx.doi.org/10.1186/s12929-015-0210-7
- ↑ Staring J, von Castelmur E, Blomen VA, van den Hengel LG, Brockmann M, Baggen J, Thibaut HJ, Nieuwenhuis J, Janssen H, van Kuppeveld FJ, Perrakis A, Carette JE, Brummelkamp TR. PLA2G16 represents a switch between entry and clearance of Picornaviridae. Nature. 2017 Jan 19;541(7637):412-416. doi: 10.1038/nature21032. Epub 2017 Jan, 11. PMID:28077878 doi:http://dx.doi.org/10.1038/nature21032
- ↑ Golczak M, Sears AE, Kiser PD, Palczewski K. LRAT-specific domain facilitates vitamin A metabolism by domain swapping in HRASLS3. Nat Chem Biol. 2015 Jan;11(1):26-32. doi: 10.1038/nchembio.1687. Epub 2014 Nov, 10. PMID:25383759 doi:http://dx.doi.org/10.1038/nchembio.1687
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