Structural Basis for the Recognition of Oxidized Phospholipids in Oxidized Low Density Lipoproteins by Class B Scavenger Receptors CD36 and SR-BI

Detao Gao,Mohammad Z Ashraf,Niladri S Kar,De Lin,Lawrence M Sayre,Eugene A Podrez

doi:10.1074/jbc.m109.082800

Detao Gao, Mohammad Z Ashraf + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m109.082800

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Abstract

Specific oxidized phospholipids (oxPC(CD36)) accumulate in vivo at sites of oxidative stress and serve as high affinity ligands for scavenger receptors class B (CD36 and SR-BI). Recognition of oxPC(CD36) by scavenger receptors plays a role in several pathophysiological processes. The structural basis for the recognition of oxPC(CD36) by CD36 and SR-BI is poorly understood. A characteristic feature of oxPC(CD36) is an sn-2 acyl group that incorporates a terminal gamma-hydroxy (or oxo)-alpha,beta-unsaturated carbonyl. In the present study, a series of model oxidized phospholipids were designed, synthesized, and tested for their ability to serve as ligands for CD36 and SR-BI. We demonstrated that intact the sn-1 hydrophobic chain, the sn-3 hydrophilic phosphocholine or phosphatidic acid group, and the polar sn-2 tail are absolutely essential for high affinity binding. We further found that a terminal negatively charged carboxylate at the sn-2 position suffices to generate high binding affinity to class B scavenger receptors. In addition, factors such as polarity, rigidity, optimal chain length of sn-2, and sn-3 positions and negative charge at the sn-3 position of phospholipids further modulate the binding affinity. We conclude that all three positions of oxidized phospholipids are essential for the effective recognition by scavenger receptors class B. Furthermore, the structure of residues in these positions controls the affinity of the binding. The present studies suggest that, in addition to oxPC(CD36), other oxidized phospholipids observed in vivo may represent novel ligands for scavenger receptors class B.

Highlights

Initial studies have demonstrated that the sn-2 acyl group of oxPCCD36 that incorporates a terminal ␥-hydroxy-␣,␤unsaturated carbonyl is essential for high affinity binding to CD36 [3]
We demonstrated that a negative carboxylate at the terminal of sn-2 position of glycerophospholipid is sufficient to generate high binding affinity to class B scavenger receptors
A Terminal Carboxylate Group in the sn-2 Position of Phospholipids Engenders High Binding Activity to Scavenger Receptor Class B—Our recent observations indicated that the negative charge on the phospholipid is crucial for the binding activity to CD36 [6]

Summary

Introduction

Initial studies have demonstrated that the sn-2 acyl group of oxPCCD36 that incorporates a terminal ␥-hydroxy (or oxo)-␣,␤unsaturated carbonyl is essential for high affinity binding to CD36 [3]. A series of phospholipids having various functional groups at sn-1, -2, and -3 positions was designed, synthesized, and used to elucidate the structural basis for the recognition of oxPCCD36 by scavenger receptors CD36 and SR-BI. We demonstrated that a negative carboxylate at the terminal of sn-2 position of glycerophospholipid is sufficient to generate high binding affinity to class B scavenger receptors.

Results

Conclusion