Effect of end group blockage on the properties of a class A amphipathic helical peptide

Venkatachalapathi, Y. V.; Phillips, Michael C.; Epand, Richard M.; Epand, Raquel F.; Tytler, Ewan M.; Segrest, Jere P.; Anantharamaiah, G.M.

doi:10.1002/prot.340150403

Cited by 122 publications

(106 citation statements)

References 37 publications

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“…It has been shown previously that the end group blockage increases the helical content of the unblocked peptide 18A by removing the destabilizing interactions of the helix macrodipole with the charged termini (13). It is worthy of note that in an ␣-helix the N terminus acetyl and the C terminus amide blocking groups also provide for the formation of two additional hydrogen bonds (one at each end) between residues i (acceptor) and i ϩ 4 (donor), compared with the unblocked peptide.…”

Section: Discussionmentioning

confidence: 94%

“…This sequence does not possess any sequence homology with any of the exchangeable apolipoproteins, but the synthetic peptide 18A was able to form peptide-lipid complexes similar to apoAI⅐lipid complexes (11,12). Adding an acyl group to the amino terminus of this peptide and an amide to the C-terminal end resulted in Ac-18A-NH 2 (also known as 2F, since the nonpolar face possesses two Phe residues) with increased ␣ helicity and affinity for lipids (13). Recently, we determined the structure of this peptide in 50% (v/v) trifluoroethanol (14) and complexed to lipid (15) using high resolution solution NMR methods.…”

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confidence: 99%

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Effect of Leucine to Phenylalanine Substitution on the Nonpolar Face of a Class A Amphipathic Helical Peptide on Its Interaction with Lipid

Mishra

Palgunachari

Krishna

et al. 2008

Journal of Biological Chemistry

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with Phe residues produced the peptide 4F (so named because of four phenylalanines), which has been extensively studied for its anti-inflammatory and antiatherogenic properties. Like 2F, 4F also forms discoidal nascent high density lipoprotein-like particles with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). Since subtle structural changes in the peptide-lipid complexes have been shown to be responsible for their antiatherogenic properties, we undertook high resolution NMR studies to deduce detailed structure of 4F in 4F⅐DMPC discs. Like 2F, 4F adopts a well defined amphipathic ␣-helical structure in association with the lipid at a 1:1 peptide/lipid weight ratio. Nuclear Overhauser effect (NOE) spectroscopy revealed a number of intermolecular close contacts between the aromatic residues in the hydrophobic face of the helix and the lipid acyl chain protons. Similar to 2F, the pattern of observed peptide-lipid NOEs is consistent with a parallel orientation of the amphipathic ␣ helix, with respect to the plane of the lipid bilayer, on the edge of the disc (the belt model). However, in contrast to 2F in 2F⅐DMPC, 4F in the 4F⅐DMPC complex is located closer to the lipid headgroup as evidenced by a number of NOEs between 4F and DMPC headgroup protons. These NOEs are absent in the 2F⅐DMPC complex. In addition, the conformation of the DMPC sn-3 chain in 4F⅐DMPC complex is different than in the 2F⅐DMPC complex as evidenced by the NOE between lipid 2.CH and ␤CH 2 protons in 4F⅐DMPC, but not in 2F⅐DMPC, complex. Based on the results of this study, we infer that the antiatherogenic properties of 4F may result from its preferential interaction with lipid headgroups.Class A amphipathic helical peptides have been shown to mimic apolipoprotein A-I (apoA-I), 3 the major protein accounting for 70% of the total protein present in high density lipoproteins (HDL). Epidemiological studies have established an inverse correlation between the plasma levels of HDL cholesterol and the risk of coronary artery disease. Reconstituted HDL of human apoA-I in combination with phospholipid has been shown to inhibit atherosclerosis in animal models of atherosclerosis (1-6) as well as in humans (7).ApoA-I mimetic peptides may represent an alternative to apoA-I for large scale production of synthetic HDL as a therapeutic agent. The motif that is responsible for the association of apoA-I with lipid was determined as tandem repeating amphipathic ␣-helical domains that are present throughout the sequence of apoA-I. The observation that the amphipathic ␣-helical domains in exchangeable apolipoproteins possess a class A amphipathic motif with basic amino acid residues at the polar-nonpolar interface and negatively charged residues at the center of the polar face (8 -10) led us to design the first model * This work was supported, in whole or in part, by National Institutes of Health Grants RO1HL089328, PO1 HL34343 (NHLBI) and CA-13148 (NCI). The 600-MHz CryoProbe was funded by 1S10RR021064-01A1 (NCRR, National Institutes of Health). This research be...

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

Effect of Leucine to Phenylalanine Substitution on the Nonpolar Face of a Class A Amphipathic Helical Peptide on Its Interaction with Lipid

Mishra

Palgunachari

Krishna

et al. 2008

Journal of Biological Chemistry

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“…The apoA-I 8 -33 and 8 -33/G26R peptides were synthesized by the solid-phase method with Fmoc (N-(9-fluorenyl)methoxycarbonyl) chemistry. The amino and carboxyl termini were capped with an acetyl group and an amide group, respectively, to promote ␣-helix formation (40). Peptide purity was verified by analytical HPLC (Ͼ97%) and mass spectrometry.…”

Section: Methodsmentioning

confidence: 99%

Amyloidogenic Mutation Promotes Fibril Formation of the N-terminal Apolipoprotein A-I on Lipid Membranes

Mizuguchi

Ogata

Mikawa

et al. 2015

Journal of Biological Chemistry

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Background:The N-terminal fragment of amyloidogenic apoA-I mutants deposits as fibrils by unknown mechanisms. Results: The G26R mutation partially prevents helix formation of the N-terminal fragment upon lipid binding, thereby facilitating ␤-transition and fibril formation. Conclusion: Membrane binding modulates fibril formation of apoA-I through partially destabilized helical conformation. Significance: The results reveal a new pathway for amyloid fibril formation by apoA-I.

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“…The model peptide 18A was thus able to mimic many of the properties of apoA-I. Refinements in peptide design showed that addition of an acetyl group at the amino terminus and an amide at the carboxyl terminus of 18A (Ac-18A-NH 2 ) increased the helicity of the peptide in solution and when associated with lipid [74]. By blocking N-and C-terminal ends of the peptide, the efficiency of Ac-18A-NH 2 for associating with phospholipids.…”

Section: Apoa-i Mimetic Peptide Designmentioning

confidence: 99%

Vasculoprotective Effects of Apolipoprotein Mimetic Peptides: An Evolving Paradigm in HDL Therapy

White¹,

Datta²,

Mochon³

et al. 2009

VDP

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Anti-atherogenic effects of high density lipoprotein (HDL) and its major protein component apolipoprotein A-I (apoA-I) are principally thought to be due to their ability to mediate reverse cholesterol transport. These agents also possess anti-oxidant properties that prevent the oxidative modification of low density lipoprotein (LDL) and anti-inflammatory properties that include inhibition of endothelial cell adhesion molecule expression. Results of the Framingham study revealed that a reduction in HDL levels is an independent risk factor for coronary artery disease (CAD). Accordingly, there has been considerable interest in developing new therapies that specifically elevate HDL cholesterol. However, recent evidence suggests that increasing circulating HDL cholesterol levels alone is not sufficient as a mode of HDL therapy. Rather, therapeutic approaches that increase the functional properties of HDL may be superior to simply raising the levels of HDL per se. Our laboratory has pioneered the development of synthetic, apolipoprotein mimetic peptides which are structurally and functionally similar to apoA-I but possess unique structural homology to the lipid-associating domains of apoA-I. The apoA-I mimetic peptide 4F inhibits atherogenic lesion formation in murine models of atherosclerosis. This effect is related to the ability of 4F to induce the formation of pre-β HDL particles that are enriched in apoA-I and paraoxonase. 4F also possesses anti-inflammatory and anti-oxidant properties that are independent of its effect on HDL quality per se. Recent studies suggest that 4F stimulates the expression of the antioxidant enzymes heme oxygenase and superoxide dismutase and inhibits superoxide anion formation in blood vessels of diabetic, hypercholesterolemic and sickle cell disease mice. The goal of this review is to discuss HDL-dependent and -independent mechanisms by which apoA-I mimetic peptides reduce vascular injury in experimental animal models.

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Effect of end group blockage on the properties of a class A amphipathic helical peptide

Cited by 122 publications

References 37 publications

Effect of Leucine to Phenylalanine Substitution on the Nonpolar Face of a Class A Amphipathic Helical Peptide on Its Interaction with Lipid

Effect of Leucine to Phenylalanine Substitution on the Nonpolar Face of a Class A Amphipathic Helical Peptide on Its Interaction with Lipid

Amyloidogenic Mutation Promotes Fibril Formation of the N-terminal Apolipoprotein A-I on Lipid Membranes

Vasculoprotective Effects of Apolipoprotein Mimetic Peptides: An Evolving Paradigm in HDL Therapy

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