Solution Structures of FcεRI α-Chain Mimics:  A β-Hairpin Peptide and Its Retroenantiomer

McDonnell, James M.; Fushman, David; Cahill, Sean M.; Sutton, Brian J.; Cowburn, David

doi:10.1021/ja963884o

Cited by 42 publications

(33 citation statements)

References 43 publications

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“…Indeed, several groups have observed that retroenantiomeric peptides may display comparable biological activities as the parent peptides (Chorev and Goodman, 1993). In line with this, the structural evaluation of a cyclic Fcε RI α-chain-derived peptide and its retro-inverso motif by NMR showed similarity of the surface topology of both compounds (McDonnell et al, 1997). However, as demonstrated by Wermuth et al (1997), the topology of the α v β 3 integrin inhibitor cyclo (-RGDfV-) and its retro-inverso peptide can differ, resulting in different activity profiles of the derivative or even complete loss of biological activity.…”

Section: Other Cyclic Upa-derived Peptide Variantsmentioning

confidence: 57%

Cyclo19,31[D-Cys19]-uPA19-31 Is a Potent Competitive Antagonist of the Interaction of Urokinase-Type Plasminogen Activator with Its Receptor (CD87)

Magdolen

Bürgle²,

Na³

et al. 2001

Biological Chemistry

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IntroductionThe serine proteases urokinase-type plasminogen activator (uPA) and plasmin, in concert with other proteolytic enzymes (e. g. matrix metalloproteases, cysteine proteases), are involved in tumor-associated processes such as cell invasion and regulation of cell/cell and cell/matrix contacts Schmitt et al., 2000;Andreasen et al., 2000). (pro-)uPA binds to a specific, high-affinity cell surface receptor, uPAR (CD87), which is composed of three structurally homologous, independently folded domains (Dear and Medcalf, 1998). In addition, there are also cellular binding sites for plasmin(ogen) (Félez, 1998). In consequence, binding of (pro-) uPA to cell membrane-anchored uPAR significantly increases plasmin generation due to a distinct increase of reciprocal activation of pro-uPA and plasminogen (Ellis et al., 1991). Plasmin not only degrades a variety of components of the extracellular matrix (e. g. fibrin and laminin), but also activates certain matrix metalloproteases (in addition to pro-uPA) which break down additional structural proteins of the extracellular matrix such as various collagens. Thus, cell surface-triggered plasminogen activation plays a fundamental role in tissue remodeling, which is a prerequisite for tumor cell invasion and metastasis Schmitt et al., 2000;Andreasen et al., 2000).The interaction of pro-uPA or its activated form high molecular weight (HMW-)uPA with uPAR has been characterised in detail. Although the N-terminal domain I of uPAR contains major determinants for uPA-binding, high affinity interaction with uPA is dependent on the multidomain structure of the receptor, indicating that all three protein domains are involved in the formation of a composite ligand binding site (Ploug, 1998;Gårdsvoll et al., 1999;Bdeir et al., 2000). In contrast, uPA binds to uPAR via a defined continuous peptide sequence

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Section: Other Cyclic Upa-derived Peptide Variantsmentioning

confidence: 57%

Cyclo19,31[D-Cys19]-uPA19-31 Is a Potent Competitive Antagonist of the Interaction of Urokinase-Type Plasminogen Activator with Its Receptor (CD87)

Magdolen

Bürgle²,

Na³

et al. 2001

Biological Chemistry

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“…Several studies on retro-peptides have been reported (32,33), but with the exception of a 13-residue retro-D-peptide (34), detailed structural analysis has generally been hampered by the inability of the retro-peptides to form stable threedimensional structures. This inability has led to the conclusion that retro-peptides differ considerably from their parent peptides and represent new structural entities where the correct folding is not guaranteed (35).…”

Section: Resultsmentioning

confidence: 99%

The retro -GCN4 leucine zipper sequence forms a stable three-dimensional structure

Mittl

Deillon

Sargent

et al. 2000

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

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The question of whether a protein whose natural sequence is inverted adopts a stable fold is still under debate. We have determined the 2.1-Å crystal structure of the retro-GCN4 leucine zipper. In contrast to the two-stranded helical coiled-coil GCN4 leucine zipper, the retro-leucine zipper formed a very stable, parallel four-helix bundle, which now lends itself to further structural and functional studies. Since the early folding experiments by Anfinsen (1), it has been accepted that structure and function of a protein are determined by its amino acid sequence as read from the N terminus to the C terminus. But how does the structure change if the amino acid sequence of the protein is inverted? Inverted sequences are occasionally found in genomic DNA, but thus far, a native retro-protein has not been detected. Physicochemical properties that are related to the amino acid composition or the hydrophobicity profile should not be affected by the inversion of the sequence, supporting the idea that retro-sequences might fold into a native-like conformation. Modeling experiments suggested that reversal of the backbone direction may result in a topological mirror image of the native structure of the protein (2) or may produce the same topology as that of the parent protein (3, 4). Thus far, no structure elucidation of a retro-Lpeptide at atomic resolution has been reported.Coiled coils, including leucine zippers, consist of two to five intertwined ␣-helices and are frequently found in oligomeric proteins such as transcription factors as well as motility and structural proteins (5). We used the two-stranded coiled-coil domain of the yeast transcription activator GCN4 (6) to dimerize an artificial HIV enhancer-binding peptide, an operation that resulted in increased inhibition of HIV enhancer-controlled transcription (7). Because modeling studies suggested that the retro-sequence of the GCN4 leucine zipper also seemed to form a suitable dimerization module, a 35-residue retro-GCN4 was synthesized and characterized. Oxidized retro-leucine zipper extended with Cys-Gly-Gly, previously termed (r-LZ38) 2 (r-GCN4-p1Ј; Fig. 1A), crystallized and is now shown by x-ray structure analysis to fold into a parallel tetrameric coiled coil. Materials and MethodsUltracentrifugation. Sedimentation velocity experiments were performed with a Beckman-Spinco XL-A analytical ultracentrifuge. The peptide was dissolved in 20 mM Tris⅐HCl͞80 mM NaCl adjusted to pH 5.0, and measurements were made over a 10-to 100-M peptide concentration range. The centrifuge was operated at a speed of 50,000 rpm at 20°C. A partial specific volume, v 20 ϭ 0.74 cm 3 ⅐g Ϫ1, was calculated from the amino acid composition as was an estimate of the degree of hydration, d 1 ϭ 0.47 g water͞g protein. Sedimentation velocity traces were analyzed according to the method described in ref. 8, and a value of the sedimentation coefficient, s w,20 ϭ 1.77 Ϯ 0.5 Svedberg, was obtained by extrapolation to infinite dilution. The axial ratio was calculated as described in ref. 9.Crysta...

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“…Final Comments-Very few studies describing the structures of a peptide and its retro-enantiomer have been reported so far (10,24,25). It has been generally observed that the structures of L-peptides and their respective retro-inverso analogues are similar but not identical.…”

Section: Resultsmentioning

confidence: 99%

Solution Structure of a Retro-inverso Peptide Analogue Mimicking the Foot-and-Mouth Disease Virus Major Antigenic Site

Petit¹,

Benkirane²,

Guichard³

et al. 1999

Journal of Biological Chemistry

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The antigenic activity of a 19-mer peptide corresponding to the major antigenic region of foot-and-mouth disease virus and its retro-enantiomeric analogue was found to be completely abolished when they were tested in a biosensor system in trifluoroethanol. This suggests that the folding pattern, which is ␣-helix in trifluoroethanol (confirmed by CD measurement), does not correspond to the biologically relevant conformation(s) recognized by antibodies. The NMR structures of both peptides were thus determined in aqueous solution. These studies showed that the two peptides exhibit similar folding features, particularly in their C termini. This may explain in part the cross-reactive properties of the two peptides in aqueous solution. However, the retro-inverso analogue appears to be more rigid than the parent peptide and contains five atypical ␤-turns. This feature may explain why retro-inverso foot-andmouth disease virus peptides are often better recognized than the parent peptide by anti-virion antibodies.The major immunogenic site of foot-and-mouth disease virus (FMDV), 1 which is contained in the so-called G-H loop comprising amino acid residues 135-158 of capsid protein VP1 (viral capsid protein 1), is located in a disordered region on the surface of the particle (1). A single inoculum of a peptide corresponding to this region usually elicits levels of neutralizing antibodies that protect guinea pigs against a severe challenge with the cognate virus (2). In some instances, however, although the total reactivity of antibodies evaluated in immunochemical tests such as enzyme-linked immunosorbent assay is high, the level of neutralizing antibodies is low. This important problem has generated numerous studies aimed at enhancing the immunogenicity of this peptide with the hope of developing a peptide construct that could be used successfully as a synthetic vaccine (3). Recently, we have shown that antisera raised in rabbits against peptides corresponding to the sequence 141-159 of two variants of serotype A cross-reacted strongly with the corresponding retro-inverso analogue peptides. Most importantly, the retro-inverso analogues, also called retro all-D or retro-enantio peptides (4, 5), induced greater and longer-lasting antibody titers than did the respective parent peptides (6). Moreover, we showed with the FP variant analogue (which contains Phe and Pro residues at positions 148 and 153, respectively) that a single inoculation of the retro-inverso peptide elicited high levels of neutralizing antibodies that persisted longer than those induced against the corresponding L-peptide and protected guinea pigs challenged with the cognate virus (7). The enhanced immunogenic reactivities of retro-inverso analogues may result from their higher resistance to proteolysis in biological fluids (7). However, this property does not explain why in immunochemical assays, retro-inverso peptides are often better recognized than the parent peptide by anti-virus, anti-protein, or anti-peptide antibodies with equilibrium affinity cons...

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Solution Structures of FcεRI α-Chain Mimics: A β-Hairpin Peptide and Its Retroenantiomer

Cited by 42 publications

References 43 publications

Cyclo19,31[D-Cys19]-uPA19-31 Is a Potent Competitive Antagonist of the Interaction of Urokinase-Type Plasminogen Activator with Its Receptor (CD87)

Cyclo19,31[D-Cys19]-uPA19-31 Is a Potent Competitive Antagonist of the Interaction of Urokinase-Type Plasminogen Activator with Its Receptor (CD87)

The retro -GCN4 leucine zipper sequence forms a stable three-dimensional structure

Solution Structure of a Retro-inverso Peptide Analogue Mimicking the Foot-and-Mouth Disease Virus Major Antigenic Site

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