Single Proline Residues can Dictate the Oxidative Folding Pathways of Cysteine-rich Peptides

Boulègue, Cyril; Milbradt, Alexander G.; Renner, Christian; Moröder, Luis

doi:10.1016/j.jmb.2006.02.031

Cited by 26 publications

(29 citation statements)

References 54 publications

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“…[24][25][26][27] While the activation energy of proline isomerization thus is unchanged upon the GSSG-catalyzed formation of disulfide-bridged cycles, the folding reaction proceeds remarkably fast, within a few minutes near room temperature (Figure 5(c) and (d)). This corroborates the notion from MD 22 and NMR studies on cyclic disulfide-bridged peptides 25 that peptidylprolyl cis-trans and trans-cis isomerization may be accelerated upon oxidative collapse, which thus may function as a built-in catalyst in the oxidative folding of prototypical CRD domains.…”

Section: Determinant Residues In the Folding Of Nematocyst Crds To DIsupporting

confidence: 87%

“…Previous studies had suggested that different propensities for the formation of cis-peptide bonds at P18 explain the structural differences between the different CRD folds. Notably though, favouring the trans over the cis proline conformation with a (4R)-fluoroproline analogue did not suffice to switch the structure of the prototypical domain structure, 22 most likely due to the only weakly increased stabilization of the trans form by 0.2 kcal/mol relative to unsubstituted proline. Inspection of CRD sequences further suggests that sequences assuming the prototypical CRD fold are not optimized for an especially high Xaa-Pro cis prolyl propensity.…”

Section: Determinant Residues In the Folding Of Nematocyst Crds To DImentioning

confidence: 91%

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Sequence–Structure and Structure–Function Analysis in Cysteine-rich Domains Forming the Ultrastable Nematocyst Wall

Meier

Jensen

Adamczyk

et al. 2007

Journal of Molecular Biology

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Section: Determinant Residues In the Folding Of Nematocyst Crds To DIsupporting

confidence: 87%

Section: Determinant Residues In the Folding Of Nematocyst Crds To DImentioning

confidence: 91%

Sequence–Structure and Structure–Function Analysis in Cysteine-rich Domains Forming the Ultrastable Nematocyst Wall

Meier

Jensen

Adamczyk

et al. 2007

Journal of Molecular Biology

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“…The resultant conformational isomerization can potentially disrupt the native structure and lead to misfolding in disulfide-rich peptides (62). We have incorporated both 4-(R)-fluoroproline (Fig.…”

Section: Design and Synthesis Of ␣-Conotoxinmentioning

confidence: 99%

Rational Design of α-Conotoxin Analogues Targeting α7 Nicotinic Acetylcholine Receptors

Armishaw

Jensen

Balle

et al. 2009

Journal of Biological Chemistry

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Nicotinic acetylcholine receptors (nAChRs) are ligandgated ion channels that belong to the superfamily of Cys loop receptors. Valuable insight into the orthosteric ligand binding to nAChRs in recent years has been obtained from the crystal structures of acetylcholine-binding proteins (AChBPs) that share significant sequence homology with the amino-terminal domains of the nAChRs. ␣-Conotoxins, which are isolated from the venom of carnivorous marine snails, selectively inhibit the signaling of neuronal nAChR subtypes. Co-crystal structures of ␣-conotoxins in complex with AChBP show that the side chain of a highly conserved proline residue in these toxins is oriented toward the hydrophobic binding pocket in the AChBP but does not have direct interactions with this pocket. In this study, we have designed and synthesized analogues of ␣-conotoxins ImI and PnIA[A10L], by introducing a range of substituents on the Pro 6 residue in these toxins to probe the importance of this residue for their binding to the nAChRs. Pharmacological characterization of the toxin analogues at the ␣ 7 nAChR shows that although polar and charged groups on Pro 6 result in analogues with significantly reduced antagonistic activities, analogues with aromatic and hydrophobic substituents in the Pro 6 position exhibit moderate activity at the receptor. Interestingly, introduction of a 5-(R)-phenyl substituent at Pro 6 in ␣-conotoxin ImI gives rise to a conotoxin analogue with a significantly higher binding affinity and antagonistic activity at the ␣ 7 nAChR than those exhibited by the native conotoxin. Nicotinic acetylcholine receptors (nAChRs)6 belong to the superfamily of Cys loop ligand-gated ion channels, which also includes serotonin (5-hydroxytryptamine, 5-HT 3 ), ␥-aminobutyric acid type A, and glycine receptors (1). As presynaptic heteroreceptors, nAChRs regulate the release of several important neurotransmitters, including dopamine, glutamate, and ␥-aminobutyric acid. Postsynaptic nAChRs are crucial mediators of the fast excitatory cholinergic neurotransmission in the central and peripheral nervous systems, which also influence the activity in several other important neurotransmitter systems (2, 3). The nAChRs are pentameric complexes composed of combinations of ␣ 1-10 , ␤ 1-4 , ␦, and ⑀/␥ subunits, each consisting of an extracellular ligand binding domain, four transmembrane helices, and an extended intracellular region arranged around a central cation-conducting pore (2). Muscle-type nAChRs are composed of two ␣ 1 -subunits and ␤ 1 -, ␦-, and ⑀/␥-subunits, whereas neuronal nAChRs are either heteromeric combinations of ␣ 2-6 -and ␤ 2-4 -subunits, ␣ 9 ␣ 10 complexes, or homomeric complexes consisting exclusively of ␣ 7 -or ␣ 9 -subunits (4). The different nAChR subtypes are involved in a wide range of distinct physiological functions, and the vast multitude of different subunit combinations underlines the importance of developing subtype-specific ligands for nAChRs as tools for studying cholinergic neurotransmission and for determining t...

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“…The residues Asp/Glu and Arg/Lys are often found in collagens at positions X and Y, respectively (93). Although such residues reduce the triple helix stability as shown for the (GER) 15 dependent electrostatic interactions between these charged residues, and possibly by hydrogen bonding with peptide backbones and interactions with the water shell (94,116). In the model peptide of Fig.…”

Section: Homotrimeric Model Peptides With the Collagen Type III C-termentioning

confidence: 93%

“…These are rarely found in folded proteins (27,112,115), but their formation is observed in folding pathways of cysteine-rich peptides where vicinal disulfides are found in productive intermediates that readily undergo disulfide reshuffling because of the thermodynamically disfavored structure (15,27,28).…”

Section: Homotrimeric Model Peptides With the Collagen Type III C-termentioning

confidence: 99%

Natural and Artificial Cystine Knots for Assembly of Homo- and Heterotrimeric Collagen Models

Boulègue

Musiol

Götz

et al. 2008

Antioxidants & Redox Signaling

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Native collagens are molecules that are difficult to handle because of their high tendency towards aggregation and denaturation. It was discovered early on that synthetic collagenous peptides are more amenable to conformational characterization and thus can serve as useful models for structural and functional studies. Single-stranded collagenous peptides of high propensity to self-associate into triple-helical trimers were used for this purpose as well as interchain-crosslinked homotrimers assembled on synthetic scaffolds. With the growing knowledge of the biosynthetic pathways of natural collagens and the importance of their interchain disulfide crosslinks, which stabilize the triple-helical structure, native as well as de novo designed cystine knots have gained increasing attention in the assembly of triple-stranded collagen peptides. In addition, natural sequences of collagens were incorporated in order to biophysically characterize their functional epitopes. This review is focused on the methods developed over the years, and future perspectives for the production of collagen-mimicking synthetic and recombinant triple-helical homo- and heterotrimers.

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Single Proline Residues can Dictate the Oxidative Folding Pathways of Cysteine-rich Peptides

Cited by 26 publications

References 54 publications

Sequence–Structure and Structure–Function Analysis in Cysteine-rich Domains Forming the Ultrastable Nematocyst Wall

Sequence–Structure and Structure–Function Analysis in Cysteine-rich Domains Forming the Ultrastable Nematocyst Wall

Rational Design of α-Conotoxin Analogues Targeting α7 Nicotinic Acetylcholine Receptors

Natural and Artificial Cystine Knots for Assembly of Homo- and Heterotrimeric Collagen Models

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