Lectin-like oxidized low-density lipoprotein receptor (LOX-1) functions as an oligomer and oligomerization is dependent on receptor density

Matsunaga, Shigeru; Xie, Qiuhong; Kumano, Miyuki; Niimi, Setsuko; Sekizawa, Kyoko; Sakakibara, Yoshikiyo; Komba, Shiro; Machida, Sachiko

doi:10.1016/j.yexcr.2007.01.007

Cited by 30 publications

(25 citation statements)

References 40 publications

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“…It is also important to underline that multimerization and cluster organization in plasma membrane, that are important requisites for LOX-1 activity [10,23,24], may interfere with the binding of the inhibitor and can influencethe ox-LDL binding affinity. In fact, clusters develop regardless of the presence of ox-LDL and their formation is LOX-1 concentration-dependent [25]. It is worth mentioning that the residual ox-LDL binding activity is totally displaced when a 100 times excess of unlabeled ox-LDL is added to the binding solution.…”

Section: Structural Analysis Synthesis and In Vivo Inhibitory Activimentioning

confidence: 95%

Design of a novel LOX-1 receptor antagonist mimicking the natural substrate

Falconi

Ciccone

D’Arrigo

et al. 2013

Biochemical and Biophysical Research Communications

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a b s t r a c tThe lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the major receptor for oxidized lowdensity lipoprotein (ox-LDL) in endothelial cells, is overexpressed in atherosclerotic lesions. LOX-1 specific inhibitors, urgently necessary to reduce the rate of atherosclerotic and inflammation processes, are not yet available. We have designed and synthesized a new modified oxidized phospholipid, named PLAzPC, which plays to small scale the ligand-receptor recognition scheme. Molecular docking simulations confirm that PLAzPC disables the hydrophobic component of the ox-LDL recognition domain and allows the interaction of the L-lysine backbone charged groups with the solvent and with the charged/ polar residues located around the edges of the LOX-1 hydrophobic tunnel. Binding assays, in a cell model system expressing human LOX-1 receptors, confirm that PLAzPC markedly inhibits ox-LDL binding to LOX-1 with higher efficacy compared to previously identified inhibitors.

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Section: Structural Analysis Synthesis and In Vivo Inhibitory Activimentioning

confidence: 95%

Design of a novel LOX-1 receptor antagonist mimicking the natural substrate

Falconi

Ciccone

D’Arrigo

et al. 2013

Biochemical and Biophysical Research Communications

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“…LOX-1 is synthesized as a 40-kDa precursor protein, further glycosylated into its mature 52-kDa form, and then transported to the cell membrane where the protein forms a homodimer via interchain disulfide bonds or polydimers through noncovalent interactions for better oxLDL binding (3,4). Intracellular signaling events include NF-kB nuclear translocation and concomitant gene expression leading to the up-regulation of inflammatory cytokines and matrix metalloproteinases.…”

mentioning

confidence: 99%

The variable expression of lectin-like oxidized low-density lipoprotein receptor (LOX-1) and signs of autophagy and apoptosis in freshly harvested human granulosa cells depend on gonadotropin dose, age, and body weight

Vilser¹,

Hueller²,

Nowicki³

et al. 2010

Fertility and Sterility

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“…Homodimers are formed via an interchain disulfide bond between Cys 140 residues (15) that promotes noncovalent interactions leading to multimerization and ox-LDL binding facilitated by the neck region (16) and receptor density at the plasma membrane (17).…”

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confidence: 99%

The hydrophobic tunnel present in LOX-1 is essential for oxidized LDL recognition and binding

Francone

Royer

et al. 2009

Journal of Lipid Research

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Lectin-like oxidized LDL (ox-LDL) receptor-1 (LOX-1) is a type-II transmembrane protein that belongs to the C-type lectin family of molecules. LOX-1 acts as a cell surface endocytosis receptor and mediates the recognition and internalization of ox-LDL by vascular endothelial cells. Internalization of ox-LDL by LOX-1 results in a number of pro-atherogenic cellular responses implicated in the development and progression of atherosclerosis. In an effort to elucidate the functional domains responsible for the binding of ox-LDL to the receptor, a series of site-directed mutants were designed using computer modeling and X-ray crystallography to study the functional role of the hydrophobic tunnel present in the LOX-1 receptor. The isoleucine residue (I 149 ) sitting at the gate of the channel was replaced by phenylalanine, tyrosine, or glutamic acid to occlude the channel opening and restrict the docking of ligands to test its functional role in the binding of ox-LDL. The synthesis, intracellular processing, and cellular distribution of all mutants were identical to those of wild type, whereas there was a marked decrease in the ability of the mutants to bind ox-LDL. These studies suggest that the central hydrophobic tunnel that extends through the entire LOX-1 molecule is a key functional domain of the receptor and is critical for the recognition of modified LDL. Lectin-like oxidized LDL receptor-1 (LOX-1) is a member of the class E scavenger receptor family, a structurally diverse group of cell surface receptors of the innate immune system that recognize and internalize oxidized LDL (ox-LDL) in endothelial cells of large arteries (1). More recent studies have indicated that LOX-1 is expressed in other cells types, including macrophages (2), vascular smooth-muscle cells (3), and platelets (4). Its expression is not constitutive, but rather, markedly induced by proinflammatory, oxidative, and mechanical stimuli (5, 6), which leads to the activation of endothelial cells, transformation of smooth-muscle cells, and accumulation of lipids in macrophages, resulting in cellular injury and the development of atherosclerosis. Studies in animal models have provided further evidence in support of a role for LOX-1 in atherosclerosis. Overexpression of LOX-1 in mice leads to the formation of atheroma-like lesion areas (7). Conversely, its deletion sustains endothelial function and confers protection in the development of atherosclerosis in association with decreased inflammatory and pro-oxidant markers (8). Finally, human genetic studies strengthen the role of this receptor in cardiovascular disease (9-11).LOX-1 is a disulfide-linked homodimeric type II transmembrane protein with a short 34-residue cytoplasmic tail, a single transmembrane domain, and an extracellular region consisting of an 80-residue domain predicted to be a coil followed by a 130-residue C-terminal C-type lectinlike domain (CTLD) responsible for ox-LDL recognition (12)(13)(14). Homodimers are formed via an interchain disulfide bond between Cys 140 residu...

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Lectin-like oxidized low-density lipoprotein receptor (LOX-1) functions as an oligomer and oligomerization is dependent on receptor density

Cited by 30 publications

References 40 publications

Design of a novel LOX-1 receptor antagonist mimicking the natural substrate

Design of a novel LOX-1 receptor antagonist mimicking the natural substrate

The variable expression of lectin-like oxidized low-density lipoprotein receptor (LOX-1) and signs of autophagy and apoptosis in freshly harvested human granulosa cells depend on gonadotropin dose, age, and body weight

The hydrophobic tunnel present in LOX-1 is essential for oxidized LDL recognition and binding

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