Model of Biologically Active Apolipoprotein E Bound to Dipalmitoylphosphatidylcholine

Peters‐Libeu, Clare; Newhouse, Yvonne M.; Hatters, Danny M.; Weisgraber, Karl H.

doi:10.1074/jbc.m510851200

Cited by 89 publications

(115 citation statements)

References 40 publications

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“…Lipidation of apoE and its domains has only a small effect on the affinity for apoC-II fibrils, suggesting that there is limited structural change in apoE at the sites of interaction. This is consistent with models of lipoprotein-bound apoE, which suggest that helix three is curved around the lipoprotein surface, with the hydrophobic face interacting with the lipid surface (54,55). This conformation would still allow basic residues on helix three of apoE to interact with alignments of negative charges on amyloid fibrils as shown in Fig.…”

Section: Discussionsupporting

confidence: 74%

Structural Basis for the Recognition and Cross-linking of Amyloid Fibrils by Human Apolipoprotein E

Gunzburg

Perugini

Howlett

2007

Journal of Biological Chemistry

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Apolipoprotein (apo) E is a well characterized lipid-binding protein in plasma that also exists as a common nonfibrillar component of both cerebral and systemic amyloid deposits. A genetic link between a common isoform of apoE, apoE4, and the incidence of late onset Alzheimer disease has drawn considerable attention to the potential roles of apoE in amyloid-related disease. We examined the interactions of apoE with amyloid fibrils composed of apoC-II and the amyloid-␤ (A␤) peptide. Aggregates of apoE with A␤ and apoC-II are found in Alzheimer and atherosclerotic plaques, respectively. Sedimentation velocity and fibril size distribution analysis showed that apoE3 and E4 isoforms bind and noncovalently cross-link apoC-II fibrils in a similar manner. This ability to cross-link apoC-II fibrils was abolished by the dissociation of the apoE tetramer to monomers or by thrombin cleavage to yield separate N-and C-terminal domains. Preparative ultracentrifuge binding studies indicated that apoE and the isolated N-and C-terminal domains of apoE bind with submicromolar affinities to both apoC-II and A␤ fibrils. Fluorescence quenching and resonance energy transfer experiments confirmed that both domains of apoE interact with apoC-II fibrils and demonstrated that the binding of the isolated N-terminal domain of apoE to apoC-II or A␤ fibrils is accompanied by a significant conformational change with helix three of the domain moving relative to helix one. We propose a model involving the interaction of apoE with patterns of aligned residues that could explain the general ability of apoE to bind to a diverse range of amyloid fibrils.

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Section: Discussionsupporting

confidence: 74%

Structural Basis for the Recognition and Cross-linking of Amyloid Fibrils by Human Apolipoprotein E

Gunzburg

Perugini

Howlett

2007

Journal of Biological Chemistry

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“…Biochemical studies have shown that R172, a residue disordered in the structure of the lipid-free N-terminal domain, makes an important contribution to high-affinity receptor binding [23]. A model based on the 10 Å-resolution x-ray diffraction data, combined with this and other biochemical observations, suggest that R172 is repositioned close to the 140-160 helix to create the receptor-binding epitope [21]. Electron paramagnetic resonance studies of ApoE using site-directed spin labels incorporated into a series of single cysteine substitution variants surrounding R172, together with fluorescence studies using an environmentally sensitive probe, also argue that lipid association induces a structural transition of this region of the protein from random coil to alpha helix and relocation to a more hydrophobic environment, again supporting the notion that lipid interaction triggers a crucial structural transition around R172 that enables high-affinity receptor binding [24].…”

Section: Apolipoprotein Recognitionmentioning

confidence: 84%

“…The 10 Å-resolution crystal structure of a receptor-binding active ApoE-dipalmitoyl phophatidylcholine particle [21], together with more recent analysis of similar particles in solution by small angle X-ray scattering [22], shows that lipid induces global rearrangements of the helices that comprise the receptor-binding domain (Figure 4). Biochemical studies have shown that R172, a residue disordered in the structure of the lipid-free N-terminal domain, makes an important contribution to high-affinity receptor binding [23].…”

Section: Apolipoprotein Recognitionmentioning

confidence: 98%

“…13). The key features of this model are: 1) a primary interface between the conserved calcium-binding residues of the LA repeats and positively charged lysine residues on the fourth helix of the 4-helix bundle, analogous to a RAP-D3 docking site, 2) supplementary contacts provided by R172, which appears to be relocated near the basic residues of the fourth helix upon lipid association [21], and 3) avidity effects due to the recruitment of at least two copies of ApoE per binding-active particle, because two copies of ApoE are present in the crystallized, binding-active particle, and at least two LA modules are necessary to form stable complexes with ApoE [8]. Whether or not any or all features of this model are correct, of course, await the results of future structural studies.…”

Section: Apolipoprotein Recognitionmentioning

confidence: 99%

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Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers

Blacklow

2007

Current Opinion in Structural Biology

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SummaryProteins of the low-density lipoprotein receptor family transport cholesterol-carrying particles into cells, clear protease-inhibitor complexes from the circulation, participate in biological signaling cascades, and even serve as viral receptors. These receptors utilize clusters of cysteine-rich LDL receptor type-A (LA) modules to bind many of their ligands. Recent structures show that these modules typically exhibit a characteristic binding mode to recognize their partners, relying primarily on electrostatic complementarity and avidity effects. The dominant contribution of electrostatic interactions with small interface areas in these complexes allows binding to be regulated by changes in pH via at least two distinct mechanisms. The structure of the subtilisin/kexin family protease PCSK9, a newly identified molecular partner of the LDLR also implicated in LDL-cholesterol homeostasis, also raises the possibility that the LDLR and its related family members may employ other strategies for pH-sensitive binding that have yet to be uncovered.

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“…To date, apolipoprotein structures are available of the 22-kDa N-terminal domain of human/mouse apoE (14 -16), ⌬(1-43)apoAI (17) and of three intact apolipoproteins, apoAI (18), insect LpIII (19,20), and apoAII (21), all in the lipid-free state. In the lipid-bound state, only recently the first low resolution (10 Å) x-ray model has been reported of an intact apolipoprotein, apoE (22). Also reported is the three-dimensional structure and dynamics of apoCII bound to micelles derived from NMR relaxation data (23).…”

mentioning

confidence: 99%

Structure and Dynamics of Human Apolipoprotein CIII

Gangabadage

Zdunek

Tessari

et al. 2008

Journal of Biological Chemistry

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Human apolipoprotein CIII (apoCIII) is a surface component of chylomicrons, very low density lipoproteins, and high density lipoproteins. ApoCIII inhibits lipoprotein lipase as well as binding of lipoproteins to cell surface heparan sulfate proteoglycans and receptors. High levels of apoCIII are often correlated with elevated levels of blood lipids (hypertriglyceridemia). Here, we report the three-dimensional NMR structure and dynamics of human apo-CIII in complex with SDS micelles, mimicking its natural lipidbound state. Thanks to residual dipolar coupling data, the first detailed view is obtained of the structure and dynamics of an intact apolipoprotein in its lipid-bound state. ApoCIII wraps around the micelle surface as a necklace of six ϳ10-residue amphipathic helices, which are curved and connected via semiflexible hinges. Three positively charged (Lys) residues line the polar faces of helices 1 and 2. Interestingly, their three-dimensional conformation is similar to that of the low density lipoprotein receptor binding motifs of apoE/B and the receptor-associated protein. At the C-terminal side of apoCIII, an array of negatively charged residues lines the polar faces of helices 4 and 5 and the adjacent flexible loop. Sequence comparison shows that this asymmetric charge distribution along the solvent-exposed face of apoCIII as well as other structural features are conserved among mammals. This structure provides a template for exploration of molecular mechanisms by which human apoCIII inhibits lipoprotein lipase and receptor binding.Apolipoproteins consist of five major classes, apo-A 2 through -E, and several subclasses. They are designed for lipid transport in blood and are attached to lipid droplets (lipoproteins) through amphipathic helices that intercalate into the single layer of phospholipids and cholesterol covering the droplet (1-3). The apolipoproteins regulate blood lipid levels by interaction with specialized endocytotic receptors and by modulating enzyme activities and lipid exchange reactions (4). They are therefore in focus with regard to disturbances in blood lipid metabolism (dyslipidemias), which in turn are associated with metabolic disorders like obesity, insulin resistance, diabetes type 2, and cardiovascular disease.Apolipoprotein CIII (apoCIII) is the most abundant C-apolipoprotein in humans (2-4). It is found on very low density lipoproteins, chylomicrons, and high density lipoproteins (HDL). ApoCIII is predominantly expressed in liver and intestine from a gene cluster important for lipid regulation (ApoAI, -AIV, -AV, and -CIII) (4, 5). ApoCIII inhibits lipoprotein lipase (LPL) and receptor-mediated endocytosis of lipoprotein particles by competing for space at the surface of the lipoproteins and by interfering with their binding to endothelial proteoglycans and to specific lipoprotein receptors (2, 4, 6). Overexpression of apoCIII in transgenic mice leads to severely increased plasma triglyceride levels due to accumulation of very low density lipoprotein-like lipoprotein remnants w...

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Model of Biologically Active Apolipoprotein E Bound to Dipalmitoylphosphatidylcholine

Cited by 89 publications

References 40 publications

Structural Basis for the Recognition and Cross-linking of Amyloid Fibrils by Human Apolipoprotein E

Structural Basis for the Recognition and Cross-linking of Amyloid Fibrils by Human Apolipoprotein E

Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers

Structure and Dynamics of Human Apolipoprotein CIII

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