Biochemistry and cell biology of mammalian scavenger receptors

Abstract

Scavenger receptors are integral membrane proteins that bind a wide variety of ligands including modified or oxidised low-density lipoproteins, apoptotic cells and pathogens. Modified low-density lipoprotein accumulation is thought to be an early event in vascular disease and thus scavenger receptor function is critical in this context. The scavenger receptor family has at least eight different subclasses (A–H) which bear little sequence homology to each other but recognize common ligands. Here we review our current understanding of the scavenger receptor subclasses with emphasis on their genetics, protein structure, biochemical properties, membrane trafficking, intracellular signalling and links to disease states. We also highlight emerging areas where scavenger receptors play roles in cell and animal physiology.

Introduction

Vascular diseases account for nearly 50% of the mortality rate in industrialised countries and are rapidly becoming a major burden in large populous countries, such as India and China [1]. Keynote studies by Brown and Goldstein led to the discovery that some patients with familial hypercholesterolaemia have mutations in the low-density lipoprotein receptor (LDL-R) that binds low-density lipoprotein (LDL) [2]. The link between elevated levels of serum LDL and cholesterol in heart disease was further strengthened by the discovery that modified LDL uptake by macrophages is linked to foam cell formation in vitro [3]. These cholesterol-filled foam cells are a major constituent of atherosclerotic plaques and lesions that form within the walls of blood vessels.

Modified LDLs are thus implicated as early causative agents in vascular disease. LDL deposits, which accumulate in vascular tissues under pathological conditions, are rapidly converted to modified or oxidised LDL (OxLDL) via nucleophilic attack by reactive molecular species that include superoxide, hydrogen peroxide and hydroxyl radicals. These reactive species are generated by the endothelium, smooth muscle tissue and migratory lymphocytes [4]. LDL modification involves changes to both protein and non-protein moieties on the LDL particle [5], [6]. Central to the oxidation of LDL is a lipid peroxidation chain reaction initiated and driven by free radicals [7]. In this process, lipid hydroperoxides are formed that fragment to reactive aldehydes, such as malondialdehyde and 4-hydroxynonenal. These can then conjugate to the ɛ-amino groups of apoB-100 lysine residues and to amino phospholipids, such as phosphatidylethanolamine and phosphatidylserine [8]. ApoB-100 also undergoes extensive breakdown during LDL modification that is due to non-enzymatic oxidative cleavage. Histidine, lysine and proline residues are particularly susceptible to oxidative damage [9].

Modified LDL binds to a diverse range of transmembrane proteins, collectively termed scavenger receptors, which are also capable of binding a diverse variety of lipid and lipoprotein-based ligands. The scavenger receptor family can be broadly classified into eight classes (A–H) (Fig. 1). In addition to mammalian species, scavenger receptors have also been identified in nematodes and flies. In this review, we will highlight the role played by each receptor in mammalian physiology by reviewing gene organisation, tissue expression, structure, ligand specificity, membrane trafficking, intracellular signalling and pathophysiology.