Sequence‐Dependence of secondary structure formation: Conformational studies of host–guest peptides in α‐helix and β‐structure supporting media

Mutter, Manfred; Maser, F.; Altmann, Karl‐Heinz; Toniolo, Claudio; Bonora, Gian Maria

doi:10.1002/bip.360240610

Cited by 51 publications

(17 citation statements)

References 48 publications

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“…Figure 6 demonstrates that inhibitors of Ab40 and Ab42 fibrillization also inhibit the aggregation of both peptides 1 and 2; this suggests that these molecules might exert their inhibitory effects through interactions with amino acid residues of the core region AbA C H T U N G T R E N N U N G (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Our studies support the notion that identifying small molecules that target this region represent a viable strategy for identifying aggregation inhibitors of the full-length proteins.…”

Section: Discussionsupporting

confidence: 68%

“…This observation could be explained by the absence of disrupting elements (switches) within the Ab sequence to interfere with its self-assembly, and is consistent with the expected role of the flanking host sequences ((Leu-Ser) n oligomers) in promoting b-sheet formation and fibrillogenesis by AbA C H T U N G T R E N N U N G (14-24). [18] The high propensity of peptide 2 to form nonfibrillar aggregates could also explain its slow fibrillization kinetics. Early association, which is driven by AbA C H T U N G T R E N N U N G (14-24) might direct the aggregation of peptide 2 into nonfibrillar off-pathway aggregates that are then trapped and slowly converted to the normal pathway after induction of acyl migration.…”

Section: Resultsmentioning

confidence: 99%

“…These model systems are based on a host-guest system where the hydrophobic core of Ab, which comprises residues 14-24 (HQKLVFFAEDV), is flanked by two b-sheet-promoting (Leu-Ser) n [18] oligomers as host sequences. The host sequences serve the primary purpose of accelerating the fibrillization of the guest peptide.…”

Section: Introductionmentioning

confidence: 99%

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Switch‐Peptides: Design and Characterization of Controllable Super‐Amyloid‐Forming Host–Guest Peptides as Tools for Identifying Anti‐Amyloid Agents

et al. 2008

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Several amyloid‐forming proteins are characterized by the presence of hydrophobic and highly amyloidogenic core sequences that play critical roles in the initiation and progression of amyloid fibril formation. Therefore targeting these sequences represents a viable strategy for identifying candidate molecules that could interfere with amyloid formation and toxicity of the parent proteins. However, the highly amyloidogenic and insoluble nature of these sequences has hampered efforts to develop high‐throughput fibrillization assays. Here we describe the design and characterization of host–guest switch peptides that can be used for in vitro mechanistic and screening studies that are aimed at discovering aggregation inhibitors that target highly amyloidogenic sequences. These model systems are based on a host–guest system where the amyloidogenic sequence (guest peptide) is flanked by two β‐sheet‐promoting (Leu‐Ser)n oligomers as host sequences. Two host–guest peptides were prepared by using the hydrophobic core of Aβ comprising residues 14–24 (HQKLVFFAEDV) as the guest peptide with switch elements inserted within (peptide 1) or at the N and C termini of the guest peptide (peptide 2). Both model peptides can be triggered to undergo rapid self‐assembly and amyloid formation in a highly controllable manner and their fibrillization kinetics is tuneable by manipulating solution conditions (for example, peptide concentration and pH). The fibrillization of both peptides reproduces many features of the full‐length Aβ peptides and can be inhibited by known inhibitors of Aβ fibril formation. Our results suggest that this approach can be extended to other amyloid proteins and should facilitate the discovery of small‐molecule aggregation inhibitors and the development of more efficacious anti‐amyloid agents to treat and/or reverse the pathogenesis of neurodegenerative and systemic amyloid diseases.

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Section: Discussionsupporting

confidence: 68%

Section: Resultsmentioning

confidence: 99%

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Switch‐Peptides: Design and Characterization of Controllable Super‐Amyloid‐Forming Host–Guest Peptides as Tools for Identifying Anti‐Amyloid Agents

et al. 2008

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“…Therefore, it appears from these data and those from a related study (Fossati et al, submitted) that in the absence of intersubunit interactions, a structural transition from ␤-strand to ␣-helix occurs in the N-and C-terminal regions of the monomer and that the stability of these helices increases as the hydrophobic or acidic environments increase (Fossati et al, submitted). Although it could be argued that the structural transition to ␣-helix seen here may be due to the ␣-helical stabilizing effects of organic solvents such as TFE (33), there are a number of observations that support the conclusion of a genuine propensity for the M. tuberculosis Cpn10 monomer to form partially helical structures. Firstly, regions without helical propensity do not form helices even in 100% TFE (26,43), and other structures (e.g., ␤-turn and ␤-sheet) are supported by this solvent (14,15,42).…”

Section: Discussionmentioning

confidence: 71%

Mycobacterium tuberculosisChaperonin 10 Is Secreted in the Macrophage Phagosome: Is Secretion Due to Dissociation and Adoption of a Partially Helical Structure at the Membrane?

et al. 2003

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To confirm that Mycobacterium tuberculosis chaperonin 10 (Cpn10) is secreted outside the live bacillus, infected macrophages were examined by electron microscopy. This revealed that the mycobacterial protein accumulates both in the wall of the bacterium and in the matrix of the phagosomes in which ingested mycobacteria survive within infected macrophages. To understand the structural implications underlying this secretion, a structural study of M. tuberculosis Cpn10 was performed under conditions that are generally believed to mimic the membrane environment. It was found that in buffer-organic solvent mixtures, the mycobacterial protein forms two main species, namely, a partially helical monomer that prevails in dilute solutions at room temperature and a dimer that folds into a ␤-sheet-dominated structure and prevails in either concentrated protein solutions at room temperature or in dilute solutions at low temperature. A partially helical monomer was also found and was completely associated with negatively charged detergents in a micelle-bound state. Remarkably, zwitterionic lipids had no effect on the protein structure. By using N-and C-truncated forms of the protein, the C-and N-terminal sequences were identified as possessing an amphiphilic helical character and as selectively associating with acidic detergent micelles. When the study was extended to other chaperonins, it was found that human Cpn10 is also monomeric and partially helical in dilute organic solvent-buffer mixtures. In contrast, Escherichia coli Cpn10 is mostly dimeric and predominately ␤-sheet in both dilute and concentrated solutions. Interestingly, human Cpn10 also crosses biological membranes, whereas the E. coli homologue is strictly cytosolic. These results suggest that dissociation to partially helical monomers and interaction with acidic lipids may be two important steps in the mechanism of secretion of M. tuberculosis Cpn10 to the external environment.

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“…Nps-Lys(Boc)-[Lys(Boc)l,-Lys(Boc)-OChocb, y1 = 4-6, is related to the onset of an intermolecularly H-bonded /3-structure, as already shown for other medium-sized peptides [5] [9] [lo] [14-191 [2SJ [26]. The addition of more polar solvents, particularly DMSO and HMPTA, to the CH,CI, solutions of the hexa-to octapeptides is able to convert the p-structure into a solvated, statistically coiled conformation, by forming effective (peptide)N-H. .…”

Section: IVmentioning

confidence: 89%

(Cholestanyloxycarbonyl)benzyl esters as peptide substituents: Conformational properties of fully protected oligo‐L‐lysines with C‐terminal (cholestanyloxycarbonyl)benzyl and benzyl ester moieties

Toniolo

Bonora

Moretto

et al. 1986

Helvetica Chimica Acta

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This study involves L-lysine oligo peptides, protected at the N-terminus by the Nps and at the &-amino functions by Boc groups. Two series were prepared from dimer to octamer, one containing the p-[(cholestan-3/3-yloxy)carbonyl]benzyl, the other one the benzyl ester group at the C-terminus. Conformational analyses were performed by IR absorption. The occurrence of the intermolecular [i-structure in the solid state and in CHzC1, solution was demonstrated for the highest oligomers. The relative stabilities of the self-associated species were determined by adding a variety of polar solvents to the CHzC12 solutions. The cholestanyl-containing peptides have a lower propensity to self-aggregate than the bcnzyl-ester analogues. Self-aggregation and decreasing solubility run in parallel. It was also directly shown that soluble urea derivatives may disrupt intermolecular H-bonds in CH2CIz, a point of practical interest, particularly in solid-phase peptide synthesis.Introduction. ~ C-Terminal protecting groups containing the cholestanol moiety are promising tools in the synthesis and conformational analysis of peptides, since they enhance peptide solubilities in organic solvents of low polarity [ 1-51. In previous work, p -([4-(cholestan-3~-yloxy)succinyloxy]methyl} benzyl ( = Chsucb (formerly Suco)) peptide esters were mainly used, but their preparation is rather cumbersome. Therefore, other carboxyl substituents containing cholestanol were proposed [6], inter afia the p-[(cholestan-3P-yloxy)carbonyl]benzyl ( = Chocb (formerly Beco)) ester group. In the present communication, we describe two complete series of [Lys( Boc)], peptides with n = 2 to 8, both carrying at the N-terminus the Nps protecting group. At the C-terminus,

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Sequence‐Dependence of secondary structure formation: Conformational studies of host–guest peptides in α‐helix and β‐structure supporting media

Cited by 51 publications

References 48 publications

Switch‐Peptides: Design and Characterization of Controllable Super‐Amyloid‐Forming Host–Guest Peptides as Tools for Identifying Anti‐Amyloid Agents

Switch‐Peptides: Design and Characterization of Controllable Super‐Amyloid‐Forming Host–Guest Peptides as Tools for Identifying Anti‐Amyloid Agents

Mycobacterium tuberculosisChaperonin 10 Is Secreted in the Macrophage Phagosome: Is Secretion Due to Dissociation and Adoption of a Partially Helical Structure at the Membrane?

(Cholestanyloxycarbonyl)benzyl esters as peptide substituents: Conformational properties of fully protected oligo‐L‐lysines with C‐terminal (cholestanyloxycarbonyl)benzyl and benzyl ester moieties

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