Serendipitous Fatty Acid Binding Reveals the Structural Determinants for Ligand Recognition in Apolipoprotein M

Sevvana, Madhumati; Ahnström, Josefin; Egerer-Sieber, C.; Lange, Harald A.; Dahlbäck, Björn; Muller, Yves A.

doi:10.1016/j.jmb.2009.08.071

Cited by 66 publications

(58 citation statements)

References 58 publications

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“…The doubling of S1P content by effl ux indicates the saturation of S1P effl ux much below the HDL particle concentration. This can be explained by the presence of a specifi c S1P binding site in HDLs which is not saturated in HDLs isolated from plasma, such as apoM (10)(11)(12). At fi rst sight and in agreement with this explanation, we found the net S1P effl ux capacity of HDLs from Apom tg mice signifi cantly increased without reaching saturation.…”

Section: Discussionsupporting

confidence: 77%

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Apolipoprotein M modulates erythrocyte efflux and tubular reabsorption of sphingosine-1-phosphate

Sutter

Park

Othman

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words high density lipoprotein • kidney • megalin • chloride-proton exchanger ClC5 • cystinosin Sphingosine-1-phosphate (S1P) acts both as an intracellular signaling molecule and an extracellular agonist of at least fi ve different G protein-coupled receptors. By its dual functions, S1P regulates the survival, proliferation, and migration as well as the functionality of many cells, eventually in opposite directions ( 1-4 ). Therefore the absolute and relative abundance of S1P in intracellular and extracellular compartments appears to be important for its biological functionality ( 4 ).Most cells form S1P by the phosphorylation of sphingosine, a degradation product of ceramides, through sphingosine kinase and degrade S1P to phosphoethanolamine and fatty aldehyde through S1P-lyase ( 1-4 ). By contrast, not only erythrocytes and platelets, but also other cells which have low or no lyase activity, release S1P ( 4-6 ), probably by an as yet unidentifi ed ABC transporter ( 4,7,8 ). Within the plasma compartment, the majority of S1P is transported by HDLs in which it exerts many cyto-protective and anti-infl ammatory effects, for example, on endothelial cells ( 8-10 ). The enrichment of S1P in HDL has been explained by the presence of a specifi c S1P binding protein, namely apoM ( 10 ). Purifi ed and recombinant apoM binds S1P with an IC 50 of 0.9 mol/l, which is in the range of physiological S1P plasma concentrations ( 11 ). X-ray crystallography of apoM identifi ed an S1P binding domain which was confi rmed by the recombinant generation of non-S1P binding apoM mutants ( 11 ). In agreement with these physicochemical data, S1P was copurifi ed with apoM containing HDL, but not apoM-free HDL, from both human Abstract Sphingosine-1-phosphate (S1P) mediates several cytoprotective functions of HDL. apoM acts as a S1P binding protein in HDL. Erythrocytes are the major source of S1P in plasma. After glomerular fi ltration, apoM is endocytosed in the proximal renal tubules. Human or murine HDL elicited time-and dose-dependent S1P effl ux from erythrocytes. Compared with HDL of wild-type (wt) mice, S1P effl ux was enhanced in the presence of HDL from apoM transgenic mice, but not diminished in the presence of HDL from apoM knockout ( Apom ؊ / ؊ ) mice. Artifi cially reconstituted and apoM-free HDL also effectively induced S1P effl ux from erythrocytes. S1P and apoM were not measurable in the urine of wt mice. Apom ؊ / ؊ mice excreted signifi cant amounts of S1P. apoM was detected in the urine of mice with defective tubular endocytosis because of knockout of the LDL receptor-related protein, chloride-proton exchanger ClC-5 ( Clcn5 ؊ / ؊ ), or the cysteine transporter cystinosin. Urinary levels of S1P were signifi cantly elevated in Clcn5 ؊ / ؊ mice. In contrast to Apom ؊ / ؊ mice, these mice showed normal plasma concentrations for apoM and S1P. In conclusion, HDL facilitates S1P effl ux from erythrocytes by both apoMdependent and apoM-independent mechanisms...

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Section: Discussionsupporting

confidence: 77%

“…Previous work by the laboratories of Dahlbäck and colleagues and Nielssen and colleagues ( 11,12 ) identifi ed apoM as a physiologically relevant binding protein of S1P in HDLs of plasma. Our lab previously confi rmed the limiting effect of S1P per apoA-I amounts to 1/72 .…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein M modulates erythrocyte efflux and tubular reabsorption of sphingosine-1-phosphate

Sutter

Park

Othman

et al. 2014

Journal of Lipid Research

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“…This technique is compatible with a variety of biological systems and has several advantages over other methods (30)(31)(32)(33) (36), to investigate S1P binding apoM in the context of isolated human HDL and LDL particles. Sevvana et al (37) showed that S1P quenched the intrinsic fluorescence of purified recombinant human apoM with an IC 50 value of 0.9 M. This value is 45-fold and 375-fold higher (weaker binding) than the K d values reported here for S1P binding to apoM-HDL and apoM-LDL, respectively.…”

Section: Serum Albumin Affinity Experimentsmentioning

confidence: 42%

A novel approach for measuring sphingosine-1-phosphate and lysophosphatidic acid binding to carrier proteins using monoclonal antibodies and the Kinetic Exclusion Assay

Fleming

Glass

Lackie

et al. 2016

Journal of Lipid Research

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(GPCRs) (1-3). Many physiological processes, such as cell growth, differentiation, survival, motility, and angiogenesis (3), and pathophysiological processes, such as cancer, cardiovascular disease, multiple sclerosis, neuropathic pain, and fibrosis (4, 5), involve S1P or LPA signaling. The S1P and LPA pathways are validated therapeutic targets; many drugs and pharmacological agents have been developed to modulate the activity of receptors and enzymes in these pathways (1,4,6). Many of these compounds block circulating S1P and LPA from binding and activating cognate membrane-bound receptors.Circulating S1P exists primarily bound to carrier molecules, including HDL, LDL, and serum albumin. HDL is a protein-rich lipoprotein containing multiple protein constituents (7) and reportedly binds 50-70% of plasma S1P, whereas serum albumin reportedly binds 30% or more (8-10) . apoM represents the main protein component in HDL responsible for binding S1P, and the X-ray cocrystal structure of recombinant human apoM in complex with S1P has been solved (11). Human plasma contains approximately 0.9 M apoM (11, 12), where >95% of the total apoM occupies 5% of the HDL (apoM-HDL) and <2% of the LDL (apoM-LDL) in plasma (13,14); this stoichiometry results in less than 1 mol of S1P per mole of HDL in human plasma (15). S1P-associated HDL stimulates cellular Abstract Sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are bioactive signaling lysophospholipids that activate specific G protein-coupled receptors on the cell surface triggering numerous biological events. In circulation, S1P and LPA associate with specific carrier proteins or chaperones; serum albumin binds both S1P and LPA while HDL shuttles S1P via interactions with apoM. We used a series of kinetic exclusion assays in which monoclonal anti-S1P and anti-LPA antibodies competed with carrier protein for the lysophospholipid to measure the equilibrium dissociation constants (K d ) for these carrier proteins binding S1P and the major LPA species. Sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are bioactive lysophospholipids that bind and signal through multiple G protein-coupled receptors

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“…ApoM reveals 19 % homology with apoD, another apolipoprotein member of the lipocalin family (Sevvana et al 2009), and is synthesised in the liver and kidney. The binding of apoM to lipoproteins is assured by its hydrophobic N-terminal signal peptide which is retained on secreted apoM, a phenomenon atypical for plasma apolipoproteins (Axler et al 2008;Christoffersen et al 2008;Dahlback and Nielsen 2009).…”

Section: Apolipoproteinsmentioning

confidence: 99%

Structure of HDL: Particle Subclasses and Molecular Components

Kontush

Lindahl

Lhomme

et al. 2014

Handbook of Experimental Pharmacology

228

226

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Serendipitous Fatty Acid Binding Reveals the Structural Determinants for Ligand Recognition in Apolipoprotein M

Cited by 66 publications

References 58 publications

Apolipoprotein M modulates erythrocyte efflux and tubular reabsorption of sphingosine-1-phosphate

Apolipoprotein M modulates erythrocyte efflux and tubular reabsorption of sphingosine-1-phosphate

A novel approach for measuring sphingosine-1-phosphate and lysophosphatidic acid binding to carrier proteins using monoclonal antibodies and the Kinetic Exclusion Assay

Structure of HDL: Particle Subclasses and Molecular Components

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