Molecular structure of an apolipoprotein determined at 2.5-.ANG. resolution

Breiter, Deborah R.; Kanost, Michael R.; Benning, Matthew M.; Wesenberg, G.E.; Law, John H.; Wells, Michael A.; Rayment, Ivan; Holden, Hazel M.

doi:10.1021/bi00217a002

Cited by 254 publications

(246 citation statements)

References 27 publications

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“…A notable feature of the structure is the presence of longer helices than anticipated from sequence analysis and the absence of strict proline punctuation observed in ⌬1-43 apoA-I (18). Like two prolines in L. migratoria apolipophorin III (19), and several in apoA-II (20), Pro-66, -121, and -165 occur in the middle of helices. Helices A-D of the four-helix bundle are shown in Fig.…”

Section: Resultsmentioning

confidence: 84%

“…Surface hydrophobic patches on apolipoproteins, including apoA-I, have been shown to cause oligomerization in solution (21). However, except in case of apoA-II (20) and truncated apoA-I (18), such oligomerization has not been observed in apolipoprotein crystal structures (19), including in this structure (see Fig. 10, which is published as supporting information on the PNAS web site).…”

Section: Resultsmentioning

confidence: 94%

“…The four-helix parallel bundle adopted by apoA-II is through association of two disulfide bonded dimers (20). Apolipophorins from L. migratoria (19) and M. sexta (33), which form five-helix bundles, also have a similar structural organization to full-length apoA-I. Superimposition over helices 1-4 of the structures of M. sexta (97 common C ␣ atoms) and the L. migratoria (101 C ␣ atoms) yield rms deviations of 3.5 and 4 Å, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Lipid-mediated unraveling of helical bundles has been proposed for insect apolipoproteins and apoE (19,21,33). Based on hydrodynamic measurements, a similar model has also been suggested for apoA-I (26).…”

Section: Resultsmentioning

confidence: 99%

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RETRACTED: Crystal structure of human apolipoprotein A-I: Insights into its protective effect against cardiovascular diseases

Ajees

Anantharamaiah

Mishra

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

201

200

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Despite three decades of extensive studies on human apolipoprotein A-I (apoA-I), the major protein component in high-density lipoproteins, the molecular basis for its antiatherogenic function is elusive, in part because of lack of a structure of the full-length protein. We describe here the crystal structure of lipid-free apoA-I at 2.4 Å. The structure shows that apoA-I is comprised of an N-terminal four-helix bundle and two C-terminal helices. The N-terminal domain plays a prominent role in maintaining its lipid-free conformation, indicating that mutants with truncations in this region form inadequate models for explaining functional properties of apoA-I. A model for transformation of the lipid-free conformation to the high-density lipoprotein-bound form follows from an analysis of solvent-accessible hydrophobic patches on the surface of the structure and their proximity to the hydrophobic core of the four-helix bundle. The crystal structure of human apoA-I displays a hitherto-unobserved array of positively and negatively charged areas on the surface. Positioning of the charged surface patches relative to hydrophobic regions near the C terminus of the protein offers insights into its interaction with cell-surface components of the reverse cholesterol transport pathway and antiatherogenic properties of this protein. This structure provides a much-needed structural template for exploration of molecular mechanisms by which human apoA-I ameliorates atherosclerosis and inflammatory diseases.

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Section: Resultsmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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RETRACTED: Crystal structure of human apolipoprotein A-I: Insights into its protective effect against cardiovascular diseases

Ajees

Anantharamaiah

Mishra

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

201

200

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“…1 Apolipophorin III is an exchangeable apolipoprotein (17 kDa) that is present as a free water-soluble protein, or bound to the lipid surface of the major insect lipoprotein, lipophorin (6 -8). The structure of Locusta migratoria apoLp-III has been determined by x-ray crystallography (9). Its structure is described as a bundle of five amphipathic ␣-helices, where the nonpolar faces of the helices are oriented toward the protein core.…”

mentioning

confidence: 99%

Dynamics and Hydration of the α-Helices of Apolipophorin III

Soulages

Arrese

2000

Journal of Biological Chemistry

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Apolipophorin III (apoLp-III) is an exchangeable apolipoprotein whose structure is represented as a bundle of five amphipathic ␣-helices. In order to study the properties of the helical domains of apolipophorin III, we designed and obtained five single-tryptophan mutants of Locusta migratoria apoLp-III. The proteins were studied by UV absorption spectroscopy, time-resolved and steady-state fluorescence spectroscopy, and circular dichroism. Fluorescence anisotropy, near-UV CD and solute fluorescence quenching studies indicate that the Trp residues in helices 1 (N-terminal) and 5 (C-terminal) have the highest conformational flexibility. These two residues also showed the highest degree of hydration. Trp residues in helices 3 and 4 display the lowest mobility, as assessed by fluorescence anisotropy and near UV CD. The Trp residue in helix 2 is protected from the solvent but shows high mobility. As inferred from the properties of the Trp residues, helices 1 and 5 appear to have the highest conformational flexibility. Helix 2 has an intermediate mobility, whereas helices 3 and 4 appear to constitute a highly ordered domain. The model presented here predicts that the relaxation of the tertiary structure and the concomitant exposure of the hydrophobic core take place through the disruption of the weak interhelical contacts between helices 1 and 5. To some extent, the weakness of the helix 1-helix 5 interaction would be due to the parallel arrangement of these helices.Exchangeable apolipoproteins belong to a class of proteins rich in amphipathic ␣-helical domains (1, 2). These proteins regulate the metabolism of lipids and lipoproteins in animals (3-5) and can be found associated with lipoproteins or in a lipid-free state. Several contributions to the understanding of the relationship between structure and function of exchangeable apolipoproteins have been made through the study of the insect exchangeable apolipoprotein, apolipophorin III (apoLp-III).1 Apolipophorin III is an exchangeable apolipoprotein (17 kDa) that is present as a free water-soluble protein, or bound to the lipid surface of the major insect lipoprotein, lipophorin (6 -8). The structure of Locusta migratoria apoLp-III has been determined by x-ray crystallography (9). Its structure is described as a bundle of five amphipathic ␣-helices, where the nonpolar faces of the helices are oriented toward the protein core.The binding of exchangeable apolipoproteins to the lipoprotein surface responds to changes in physical chemical properties of the lipoprotein lipid surface domain. The physiological role of apoLp-III is binding to a lipoprotein surface that has been destabilized by an excess of diacylglycerol (10 -12). The hydrophobic moment and the distribution of charged residues on the polar face of the amphipathic ␣-helices of the apolipoproteins constitute a key structural element of the exchangeable apolipoproteins (1, 2). Moreover, the thermodynamics and kinetics of the binding process are also dependent on the structure and dynamics of the apolipoprotein...

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Disposition of amphiphilic helices in heteropolar environments

Chou¹,

Zhang

Maggiora³

1997

Proteins

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It is known that alpha helices in globular proteins usually consist of two types of residues, hydrophobic and hydrophilic, with the number of each type being roughly equal. Except for many transmembrane helices, alpha-helices are generally amphiphilic to some degree. This is not entirely surprising because alpha-helices typically reside in heteropolar environments that arise from the polar aqueous solution that surrounds a protein and the apolar "hydrophobic core" located at its center. The packing of alpha-helices in such heteropolar environments is driven by the minimization of free energy brought about by placing hydrophobic sidechains into apolar environments and hydrophilic sidechains into polar environments. The interface between the two environments can be characterized by an interfacial plane, called the demarcation plane, that optimally separates the two classes of residues. The inclination angle omega between the axis of the helix and the demarcation plane provides a measure of the degree of amphiphilicity of an alpha-helix. For highly amphiphilic helices, omega approximately 0. The inclination angle provides a new measure of amphiphilicity that complements the hydrophobic moments of Eisenberg et al. Based on the simple physical model described above, an algorithm is developed for predicting the helix inclination angle. The calculated results show that the inclination angle for most alpha-helices extracted from globular proteins is less than 25 degrees in magnitude. This suggests that helices found in globular proteins tend to be reasonably amphiphilic with half their face dominated by hydrophobic residues and the other half by hydrophilic residues. A new two-dimensional representation that characterizes the disposition of hydrophobic and hydrophilic residues in alpha-helices, called a "wenxiang diagram," is presented. The wenxiang diagram can also be used as an important element to represent a protein molecule.

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Molecular structure of an apolipoprotein determined at 2.5-.ANG. resolution

Cited by 254 publications

References 27 publications

RETRACTED: Crystal structure of human apolipoprotein A-I: Insights into its protective effect against cardiovascular diseases

RETRACTED: Crystal structure of human apolipoprotein A-I: Insights into its protective effect against cardiovascular diseases

Dynamics and Hydration of the α-Helices of Apolipophorin III

Disposition of amphiphilic helices in heteropolar environments

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