Conformation and Lipid Binding of the N-Terminal (1−44) Domain of Human Apolipoprotein A-I

Zhu, Hongli L.; Atkinson, David

doi:10.1021/bi0487894

Cited by 36 publications

(53 citation statements)

References 35 publications

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“…However, binding of unstructured regions of the peptide(S) to the disk edge may compensate for the lack of helical conformation. In contrast to the ~100 Å disk like complex formed by the N-terminal peptide ( apoA-I) in which helical structure was insufficient to cover the disk edge even by a single belt [21], the compositions of complexes formed by the C-terminal peptide are more consistent with a "double belt" model, similar to that proposed for full length apoA-I [45,46].…”

Section: Lipid Interactionmentioning

confidence: 56%

“…At 4:1 or higher ratios, no free peptide was observed, and both peptide and lipid were enriched in the density range of 1.08-1.12 g/cm 3 , typical of apoA-I/DMPC discoidal complexes. This is in contrast to the N-terminal peptide ( apoA-I), in which free apoA-I always co-exists with complexes even in excess DMPC [21]. Thus, consistent with its proposed high lipid affinity, the C-terminal segment ([198-243]apoA-I) possesses a higher lipid affinity than the N-terminal segment of apoA-I.…”

Section: Lipid Interactionmentioning

confidence: 72%

“…The peptide representing the N-terminal apoA-I ( apoA-I), as characterized previously [21], was also investigated. The apparent T m , was ~ 50 °C for DMPC: apoA-I 4:1 w/w, ~ 65 °C for DMPC: apoA-I 4:1 w/w, and ~ 82 °C for DMPC:apoA-I 4:1 w/w (figure 8A), derived from the differential analysis of the thermal unfolding heating curves at the same scanning rate.…”

Section: Stability Of Complexes Formed By [198-243]apoa-i-dmpcmentioning

confidence: 99%

“…These include overlapping 44-residues peptides from the central domain ([99-142]apoA-I, [121-164]apoA-I [25], and [143-186]apoA-I). In addition, we have previously reported the unique properties of the N-terminal ( apoA-I) [21]. Here we report the conformational characterization and studies of the phospholipid interactions of a peptide that represents the extreme C-terminal of apoA-I ( apoA-I).…”

mentioning

confidence: 97%

“…A continuous helix repeat assignment describes 10 tandemly repeated helices punctuated mainly by prolines. However, although this continuous helical model is the most widely used one, assignment of the precise secondary structural distribution throughout the apoA-I sequence is far from agreement by different approaches [11,[15][16][17][18][19][20][21][22] Thus, studies of peptides [15,[23][24][25] that model different regions of apoA-I can provide important information on the roles of specific residues and segments, and their interactions in the structure and stability of the parent apolipoprotein. Analysis of the consensus sequences of the A and B repeat derived from the sequences of multiple exchangeable apolipoproteins [7], together with studies of 44-residue consensus sequence peptides, showed ~ 90% and 5 0% α-helical contents for peptides with ABAB [26] and ABBA [27] sequence ordering respectively.…”

mentioning

confidence: 99%

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Conformation and Lipid Binding of a C-Terminal (198−243) Peptide of Human Apolipoprotein A-I

Zhu

Atkinson

2007

Biochemistry

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Human apolipoprotein A-I (apoA-I) is the principle apolipoprotein of high-density lipoproteins that are critically involved in reverse cholesterol transport. The intrinsically flexibility of apoA-I has hindered studies of the structural and functional details of the protein. Our strategy is to study peptide models representing different regions of apoA-I. Our previous report on apoA-I demonstrated that this N-terminal region is unstructured and folds into ~ 60% α-helix with a moderate lipid binding affinity. We now present details of the conformation and lipid interaction of a C-terminal 46 residue peptide, apoA-I, encompassing putative helix repeats 10, 9 and the second half of repeat 8 from the C-terminus of apoA-I. Far ultraviolet circular dichroism spectra show that apoA-I is also unfolded in aqueous solution. However, self-association induces ~ 50% α-helix in the peptide. The self-associated peptide exists mainly as a tetramer, as determined by native electrophoresis, cross-linking with glutaraldehyde and unfolding data from circular dichroism (CD) and differential scanning calorimetry (DSC). In the presence of a number of lipid mimicking detergents, above their CMC, ~ 60% α-helix was induced in the peptide. In contrast, SDS, an anionic lipid mimicking detergent, induced helical folding in the peptide at a concentration of ~ 0.003% (1 00 μM), ~ 70 fold below its typical CMC (0.17-0.23% or 6-8 mM). Both monomeric and tetrameric peptide can solublize dimyristoyl phosphatidyl choline (DMPC) liposomes and fold into ~ 60% α-helix. Fractionation by density gradient ultracentrifugation and visualization by negative staining electromicroscopy, demonstrated that the peptide binds to DMPC with high affinity to form at least two sizes of relatively homogenous discoidal HDL-like particles depending on the initial lipid:peptide ratio. The characteristics (lipid:peptide w/w, diameter and density) of both complexes are similar to those of plasma A-I/DMPC formed under similar conditions: small discoidal complexes (~ 3:1 w/w, ~ 110Å and ~ 1.10g/cm 3 ) formed at initial 1:1 w/w ratio and larger discoidal complexes ( ~ 4.6:1 w/w, ~ 165 Å and ~ 1.085g/cm 3 ) formed at initial 4:1 w/w ratio. The cross-linking of the peptide on the two sizes of disks is consistent with the calculated peptide numbers per particle, which result in sufficient helix to surround the lipid bilayer twice. Thus, our data provide direct evidence that this C-terminal region of apoA-I is responsible for the self-association of apoA-I, and this Cterminal peptide model can mimic the interaction with phospholipid of plasma apoA-I to form two sizes of homogenous discoidal complexes and thus may be responsible for apoA-I function in the formation and maintenance of HDL subspecies in plasma.The plasma concentration of high-density lipoprotein (HDL) is an inverse marker of potential cardiovascular disease. The well-documented anti-atherogenic function of HDL is related to its critical role in reverse cholesterol transport, such as mediation of cholestero...

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Section: Lipid Interactionmentioning

confidence: 56%

Section: Lipid Interactionmentioning

confidence: 72%

Section: Stability Of Complexes Formed By [198-243]apoa-i-dmpcmentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

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Conformation and Lipid Binding of a C-Terminal (198−243) Peptide of Human Apolipoprotein A-I

Zhu

Atkinson

2007

Biochemistry

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Cholesterol transport and beyond: Illuminating the versatile functions of HDL apolipoproteins through structural insights and functional implications

Bhale,

Meilhac,

d'Hellencourt

et al. 2024

BioFactors

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High‐density lipoproteins (HDLs) play a vital role in lipid metabolism and cardiovascular health, as they are intricately involved in cholesterol transport and inflammation modulation. The proteome of HDL particles is indeed complex and distinct from other components in the bloodstream. Proteomics studies have identified nearly 285 different proteins associated with HDL; however, this review focuses more on the 15 or so traditionally named “apo” lipoproteins. Important lipid metabolizing enzymes closely working with the apolipoproteins are also discussed. Apolipoproteins stand out for their integral role in HDL stability, structure, function, and metabolism. The unique structure and functions of each apolipoprotein influence important processes such as inflammation regulation and lipid metabolism. These interactions also shape the stability and performance of HDL particles. HDLs apolipoproteins have multifaceted roles beyond cardiovascular diseases (CVDs) and are involved in various physiological processes and disease states. Therefore, a detailed exploration of these apolipoproteins can offer valuable insights into potential diagnostic markers and therapeutic targets. This comprehensive review article aims to provide an in‐depth understanding of HDL apolipoproteins, highlighting their distinct structures, functions, and contributions to various physiological processes. Exploiting this knowledge holds great potential for improving HDL function, enhancing cholesterol efflux, and modulating inflammatory processes, ultimately benefiting individuals by limiting the risks associated with CVDs and other inflammation‐based pathologies. Understanding the nature of all 15 apolipoproteins expands our knowledge of HDL metabolism, sheds light on their pathological implications, and paves the way for advancements in the diagnosis, prevention, and treatment of lipid and inflammatory‐related disorders.

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Evaluation of lipid‐binding properties of the N‐terminal helical segments in human apolipoprotein A‐I using fragment peptides

Tanaka

Ohta

et al. 2008

Journal of Peptide Science

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Although the N-terminal region in human apolipoprotein (apo) A-I is thought to stabilize the lipid-free structure of the protein, its role in lipid binding is unknown. Using synthetic fragment peptides, we examined the lipid-binding properties of the first 43 residues (1-43) of apoA-I in comparison with residues 44-65 and 220-241, which have strong lipid affinity in the molecule. Circular dichroism measurements demonstrated that peptides corresponding to each segment have potential propensity to form alpha-helical structure in trifluoroethanol. Spectroscopic and thermodynamic measurements revealed that apoA-I (1-43) peptide has the strong ability to bind to lipid vesicles and to form alpha-helical structure comparable to apoA-I (220-241) peptide. Substitution of Tyr-18 located at the center of the most hydrophobic region in residues 1-43 with a helix-breaking proline resulted in the impaired lipid binding, indicating that the alpha-helical structure in this region is required to trigger the lipid binding. In contrast, apoA-I (44-65) peptide exhibited a lower propensity to form alpha-helical structure upon binding to lipid, and apoA-I (44-65/S55P) peptide exhibited diminished, but not completely impaired, lipid binding, suggesting that the central region of residues 44-65 is not pivotally involved in the formation of the alpha-helical structure and lipid binding. These results indicate that the most N-terminal region of apoA-I molecule, residues 1-43, contributes to the lipid interaction of apoA-I through the hydrophobic helical residues.

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Conformation and Lipid Binding of the N-Terminal (1−44) Domain of Human Apolipoprotein A-I

Cited by 36 publications

References 35 publications

Conformation and Lipid Binding of a C-Terminal (198−243) Peptide of Human Apolipoprotein A-I

Conformation and Lipid Binding of a C-Terminal (198−243) Peptide of Human Apolipoprotein A-I

Cholesterol transport and beyond: Illuminating the versatile functions of HDL apolipoproteins through structural insights and functional implications

Evaluation of lipid‐binding properties of the N‐terminal helical segments in human apolipoprotein A‐I using fragment peptides

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