Identification of a Domain That Mediates Association of Platelet-activating Factor Acetylhydrolase with High Density Lipoprotein

Gardner, Alison A.; Reichert, Ethan C.; Topham, Matthew K.; Stafforini, Diana M.

doi:10.1074/jbc.m802394200

Cited by 55 publications

(64 citation statements)

References 60 publications

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“…The C terminus of apoB-100 could be important for LDL binding to Lp-PLA 2 ( 22 ). Although a domain on Lp-PLA 2 containing residues 367-370 has been proposed to mediate Lp-PLA 2 /HDL association ( 23 ), the detailed molecular basis of Lp-PLA 2 /HDL association is not clear. The binding interactions between Lp-PLA 2 and HDL may be involved in more than one binding region or accompany conformational changes.…”

Section: Identifi Cation Of Hdl/lp-pla 2 Binding Sites By Dxmsmentioning

confidence: 95%

“…These peptides were used to determine the deuteration level of Lp-PLA 2 . According to a reported Lp-PLA 2 /HDL binding assay ( 23 ), 800 µg of purifi ed Lp-PLA 2 was incubated with 10 mg HDL particles for at least 30 min to reach maximum binding, so we risk by the US Food and Drug Administration ( 14 ). In addition to serving as a biomarker, Lp-PLA 2 is also considered as a target for the treatment of cardiovascular disease.…”

Section: Identifi Cation Of Hdl/lp-pla 2 Binding Sites By Dxmsmentioning

confidence: 99%

See 1 more Smart Citation

Structural basis of specific interactions of Lp-PLA2 with HDL revealed by hydrogen deuterium exchange mass spectrometry

Cao¹,

Hsu²,

et al. 2013

Journal of Lipid Research

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Section: Identifi Cation Of Hdl/lp-pla 2 Binding Sites By Dxmsmentioning

confidence: 95%

Section: Identifi Cation Of Hdl/lp-pla 2 Binding Sites By Dxmsmentioning

confidence: 99%

Structural basis of specific interactions of Lp-PLA2 with HDL revealed by hydrogen deuterium exchange mass spectrometry

Cao¹,

Hsu²,

et al. 2013

Journal of Lipid Research

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“…A second short helix (residues 362-369) has hydrophobic residues positioned to insert into the hydrophobic portion of the aqueous-lipid interface. Recently, residues near this helix were predicted to be important for HDL binding (31). The predicted interfacial-binding residues of PAF-AH are displayed in Fig.…”

Section: Interface Binding Surface Of Paf-ah-the Disorder Of the Resimentioning

confidence: 99%

Crystal Structure of Human Plasma Platelet-activating Factor Acetylhydrolase

Samanta

Bahnson

2008

Journal of Biological Chemistry

111

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Human plasma platelet-activating factor (PAF) acetylhydrolase functions by reducing PAF levels as a general anti-inflammatory scavenger and is linked to anaphylactic shock, asthma, and allergic reactions. The enzyme has also been implicated in hydrolytic activities of other pro-inflammatory agents, such as sn-2 oxidatively fragmented phospholipids. This plasma enzyme is tightly bound to low and high density lipoprotein particles and is also referred to as lipoprotein-associated phospholipase A 2 . The crystal structure of this enzyme has been solved from x-ray diffraction data collected to a resolution of 1.5 Å . It has a classic lipase ␣/␤-hydrolase fold, and it contains a catalytic triad of Ser 273 , His 351 , and Asp 296 . Two clusters of hydrophobic residues define the probable interface-binding region, and a prediction is given of how the enzyme is bound to lipoproteins. Additionally, an acidic patch of 10 carboxylate residues and a neighboring basic patch of three residues are suggested to play a role in high density lipoprotein/low density lipoprotein partitioning. A crystal structure is also presented of PAF acetylhydrolase reacted with the organophosphate compound paraoxon via its active site Ser 273 . The resulting diethyl phosphoryl complex was used to model the tetrahedral intermediate of the substrate PAF to the active site. The model of interface binding begins to explain the known specificity of lipoprotein-bound substrates and how the active site can be both close to the hydrophobic-hydrophilic interface and at the same time be accessible to the aqueous phase.2 is a phospholipid messenger synthesized by a variety of cells involved in host defense, such as endothelial cells, platelets, neutrophils, monocytes, and macrophages (1). High levels of PAF are responsible for a variety of human diseases such as inflammation, asthma, necrotizing enterocolitis, and sepsis (2). The enzyme PAF-AH (EC 3.1.1.47) was first identified from the plasma by its ability to hydrolyze and therefore inactivate PAF (3).The enzyme plasma PAF-AH has been classified as group VIIA phospholipase A2 (PLA 2 ) (4), and it hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. In addition to its role in reducing PAF levels, PAF-AH functions by hydrolyzing other pro-inflammatory agents, such as oxidized lipids of LDL particles (5, 6). Many of these oxidized phospholipids have an oxidatively fragmented sn-2 chain that would orient away from the hydrophobic portion of an LDL particle. These oxidized phospholipid species are present at elevated levels at atherogenic lesions, and the PAF-AH hydrolysis of these species has attracted considerable attention recently as a potential therapeutic target (6 -10).Physiologically, plasma PAF-AH is associated to both LDL and HDL particles and therefore functions on the lipid-aqueous interface and can be considered a peripheral membrane protein. Another generally used name for plasma PAF-AH is lipoprotein-associated PLA 2 (7). Kinetic studies have shown ...

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“…Its active site is composed of a serine, histidine, and aspartic acid hydrolase triad (55), which is unlike all other PLA 2 s, which have dyads. Recent work has identified c-terminal regions of the enzyme that are required for binding to HDL and LDL (56). This enzyme was cloned from human plasma in 1995 and was shown to have anti-inflammatory activity in vivo (57).…”

Section: Secreted Plamentioning

confidence: 99%

Phospholipase A2 structure/function, mechanism, and signaling

Burke

Dennis

2009

Journal of Lipid Research

778

628

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Tremendous advances in understanding the structure and function of the superfamily of phospholipase A 2 (PLA 2 ) enzymes has occurred in the twenty-first century. The superfamily includes 15 groups comprising four main types including the secreted sPLA 2 , cytosolic cPLA 2 , calciumindependent iPLA 2 , and platelet activating factor (PAF) acetyl hydrolase/oxidized lipid lipoprotein associated (Lp)PLA 2 . We review herein our current understanding of the structure and interaction with substrate phospholipids, which resides in membranes for a representative of each of these main types of PLA 2 . We will also briefly review the development of inhibitors of these enzymes and their roles in lipid signaling.-Burke, J. E., and E. A. Dennis. Phospholipase A 2 structure/function, mechanism, and signaling. J. Lipid Res.

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Identification of a Domain That Mediates Association of Platelet-activating Factor Acetylhydrolase with High Density Lipoprotein

Cited by 55 publications

References 60 publications

Structural basis of specific interactions of Lp-PLA2 with HDL revealed by hydrogen deuterium exchange mass spectrometry

Structural basis of specific interactions of Lp-PLA2 with HDL revealed by hydrogen deuterium exchange mass spectrometry

Crystal Structure of Human Plasma Platelet-activating Factor Acetylhydrolase

Phospholipase A2 structure/function, mechanism, and signaling

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