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Mutagenesis and Homology Modeling Reveal a Predicted Pocket of Lysophosphatidylcholine Acyltransferase 2 to Catch Acyl-Coa

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Mutagenesis and Homology Modeling Reveal a Predicted Pocket of Lysophosphatidylcholine Acyltransferase 2 to Catch Acyl-Coa bioRxiv preprint doi: https://doi.org/10.1101/2020.10.31.363515; this version posted November 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Mutagenesis and homology modeling reveal a predicted pocket of lysophosphatidylcholine acyltransferase 2 to catch Acyl-CoA. Fumie Hamano1, 2, Kazuaki Matoba3, Tomomi Hashidate-Yoshida1, Tomoyuki Suzuki1, 4, Kiyotake Miura5, Daisuke Hishikawa1, 6, Takeshi Harayama1, 7, Koichi Yuki5, 8, Yoshihiro Kita2, Nobuo N. Noda3, Takao Shimizu1,3, Hideo Shindou1, 9 1Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan 2Life Sciences Core Facility, 9Department of Lipid Science, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan 3Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Research Foundation, Tokyo 141-0021, Japan 4Department of Respiratory Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. 5Department of Biochemistry and Molecular Biology, The University of Tokyo, Tokyo, 113- 0033, Japan 6Institute of Research, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo 113- 8519, Japan 7Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, Université Côte d'Azur, 06560 Valbonne, France 8Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital; Department of Anesthesia and Immunology, Harvard Medical School, MA, USA. Running title: AGPAT motifs surrounding an acyl-CoA pocket *To whom correspondence should be addressed: Hideo Shindou, National Center for Global Health and Medicine, Tokyo 162-8655, Japan. Tel.: +81-3-5273-5351, Fax: +81-3-3202-7364, e- mail: [email protected] Keywords: platelet activating factor, protein structure, LPCAT2, LPCAT1, AGPAT family 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.10.31.363515; this version posted November 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Abstract Introduction Platelet-activating factor (PAF) is a potent proinflammatory phospholipid mediator that Platelet-activating factor (PAF, 1-O-alkyl-2- elicits various cellular functions and promotes acetyl-sn-glycero-3-phosphocholine) is a several pathological conditions, including potent pro-inflammatory lipid mediator that anaphylaxis and neuropathic pain. PAF is activates the PAF receptor, which is a G biosynthesized by two types of lyso-PAF protein-coupled receptor. PAF elicits several acetyltransferases: lysophosphatidylcholine biological effects, such as platelet activation, acyltransferase 1 (LPCAT1) and LPCAT2, airway constriction, hypotension, systemic which are constitutive and inducible forms of anaphylaxis, and neuropathic pain (1, 2). In lyso-PAF acetyltransferase, respectively. response to extracellular stimuli, 1-O-alkyl-2- Because LPCAT2 mainly produces PAF under acyl-sn-glycero-3-phosphocholine is inflammatory conditions, understanding the hydrolyzed by phospholipase A2 to produce structure of LPCAT2 is important for polyunsaturated fatty acid and 1-O-alkyl-sn- developing specific drugs against PAF-related glycero-3-phosphocholine (lyso-PAF). Under inflammatory diseases. Although the structure these conditions, PAF is rapidly of LPCAT2 has not been determined, the biosynthesized from lyso-PAF by lyso-PAF crystal structure was reported for Thermotoga acetyltransferase [EC: 2.3.1.67] (3–5). maritima PlsC, an enzyme in the same enzyme family as LPCAT2. In this study, we identified Previously, we identified two types of lyso- residues in mouse LPCAT2 essential for its PAF acetyltransferases, enzymatic activity and a potential acyl- lysophosphatidylcholine acyltransferase 1 coenzyme A (CoA)-binding pocket, based on (LPCAT1) (6) and LPCAT2 (5). LPCAT1 is a homology modeling of mouse LPCAT2 with constitutively expressed lyso-PAF PlsC. We also found that Ala115 of mouse acetyltransferase that also generates LPCAT2 was important for acyl-CoA dipalmitoyl-phosphatidylcholine (PC) selectivity. In conclusion, these results predict through its LPCAT activity [EC: 2.3.1.23] (6– the structure of mouse LPCAT2. Our findings 8). Dipalmitoyl-PC is a main component of have implications for the future development pulmonary surfactant, which is essential for of new drugs against PAF-related diseases. alveolar gas exchange (9, 10). In contrast, 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.10.31.363515; this version posted November 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. LPCAT2 expression is regulated in three are essential for acyltransferase activity (6, independent manners in macrophages. In a 15–17). To develop drugs for PAF-related previous study, LPCAT2 was rapidly diseases, it is important to understand the phosphorylated and activated by protein biochemical characteristics of PAF production kinase C alpha following stimulation with and the structure of LPCAT2. However, the PAF or ATP for 1 min (11). LPCAT2 structure is unknown because it is Lipopolysaccharide stimulation for 30 min difficult to solubilize and purify LPCAT2 and 16 h induced LPCAT2 phosphorylation by from the membrane fraction of tissues or cells. MAP kinase-activated protein kinase 2 and Recently, Robertson et al. reported the crystal LPCAT2 expression (mRNA and protein), structure of Thermotoga maritima PlsC, respectively, via Toll-like receptor 4 (5, 12). which is a member of the AGPAT family and Although phosphorylation of residue Ser34 in possesses lysophosphatidic acid LPCAT2 is common, the responsible kinase acyltransferase activity (18). This report is and the time course of such phosphorylation useful for analyzing the structure of LPCAT2. are different. Thus, LPCAT2 acts as an inducible and activated form of lyso-PAF In this study, site-directed mutagenesis acetyltransferase under inflammatory revealed AGPAT motifs in mouse LPCAT2 conditions. LPCAT2 also possesses LPCAT (mLPCAT2) and important residues for its activity that catalyzes acyl-coenzyme A (CoA) acyl-CoA selectivity. Additionally, utilizing incorporation into membrane the information from the PlsC crystal, an acyl- phosphatidylcholine (PC). However, the CoA binding pocket of mLPCAT2 was biological roles of this LPCAT2 activity, predicted by homology modeling. Our data which incorporates long fatty acids remain should help in analyzing the biochemical unknown, because LPCAT2 deficient mice characteristics of mLPCAT2 and in showed reduction of PAF, but not other developing new drugs for PAF-related phospholipids (2). Whereas, it is reported that diseases. LPCAT2 produces PC at lipid droplet (13, 14). Results Both LPCAT1 and LPCAT2 are members of Alignment and homology modeling of 1-acylglycerol-3-phosphate O-acyltransferase mouse LPCAT1 (mLPCAT1), mLPCAT2, (AGPAT) family. Several groups (including and Thermotoga maritima PlsC (tmPlsC) our group) have reported AGPAT motifs that 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.10.31.363515; this version posted November 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. tmPlsC (18) is homologous to mLPCAT1 and homology in both the AGPAT motif and the mLPCAT2, and its structure is available in the predicted loop region following motif 4 (red Protein Data Bank (PDB); thus, the tmPlsC square in the loop). Homology modeling was structure was selected for predicting the performed using the tmPlsC structure (18) as structure of mLPCAT2. According to data a template (Fig. 1C, Supporting Information from the EMBOSS Water website models 1, 2). These structures show that two (https://www.ebi.ac.uk/Tools/psa/emboss_wa N-terminal α-helices, which anchor tmPlsC to ter/), tmPlsC shares 26% identity with both one leaflet of the membrane, were also mLPCAT1 and mLPCAT2. The primary predicted to be present in mLPCAT1 (residues structure of mLPCAT2 was compared with 44–112) and mLPCAT2 (residues 52–124). those of mLPCAT1 and tmPlsC (Fig. 1A). AGPAT motifs 1 to 4 are highly conserved Identification of AGPAT motifs in among all three enzymes. For homology mLPCAT2 modeling, we analyzed short forms of mLPCAT2 (residues 52–320) and mLPCAT1 Next, we evaluated the roles of the AGPAT (residues 44–301) because tmPlsC is shorter motifs and the N-terminal two-helix motif. than both mLPCAT1 and mLPCAT2 (Fig. 1B). The following Ala or Glu substitutions were Consequently, the dilysine motif (which made to prepare mLPCAT2 mutants: H146A localizes proteins to the endoplasmic and D151A in AGPAT motif 1; G176A, reticulum) and the EF-hand (like) motifs of R177A, R177E, R180A, L186A, V187A, mLPCAT1 and mLPCAT2 were not analyzed R189A, and RK195/196AA around AGPAT in this study, as tmPlsC does not possess these motif 2; P219A, E220A, G221A, and C223A motifs (Fig. 1B). Phosphorylation of the N- in AGPAT motif 3; K233A, P242A, and terminal Ser34 residue of mLPCAT2 was also P245A around AGPAT
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