A Photoinducible β-Hairpin

Aemissegger, Andreas; Kräutler, Vincent; Gunsteren, Wilfred F. van; Hilvert, Donald

doi:10.1021/ja0442567

Cited by 129 publications

(130 citation statements)

References 52 publications

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“…56,57 In addition, Hilvert has found that unlike D-ProGly type II′ turns, the type I′ reverse turns generated by cis-AMPP are more mobile and the backbone of each proximal strand of the hairpin are flipped 180°reversing the hydrogen bonding pattern relative to type II′ turns. 38 Because hairpin stability is dictated by multiple factors, including hydrogen bonding, secondary structure propensities of residues in the strands, and side chain interactions, these differences could have a profound impact on the stability of the resultant conformations and impede transition to cross-β fibrils. 38 If cis-AMPP does form a type I′ turn in the context of peptide 2, it may represent a non-native and highly stable β-hairpin conformation that precludes rotation into the nonhairpin turn found in Aβ oligomers and fibrils.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

An Azobenzene Photoswitch Sheds Light on Turn Nucleation in Amyloid-β Self-Assembly

Doran

Anderson

Latchney

et al. 2012

ACS Chem. Neurosci.

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Amyloid-β (Aβ) self-assembly into cross-β amyloid fibrils is implicated in a causative role in Alzheimer's disease pathology. Uncertainties persist regarding the mechanisms of amyloid selfassembly and the role of metastable prefibrillar aggregates. Aβ fibrils feature a sheet-turn-sheet motif in the constituent β-strands; as such, turn nucleation has been proposed as a rate-limiting step in the selfassembly pathway. Herein, we report the use of an azobenzene β-hairpin mimetic to study the role turn nucleation plays on Aβ selfassembly. [3-(3-Aminomethyl)phenylazo]phenylacetic acid (AMPP) was incorporated into the putative turn region of Aβ42 to elicit temporal control over Aβ42 turn nucleation; it was hypothesized that self-assembly would be favored in the cis-AMPP conformation if β-hairpin formation occurs during Aβ self-assembly and that the trans-AMPP conformer would display attenuated fibrillization propensity. It was unexpectedly observed that the trans-AMPP Aβ42 conformer forms fibrillar constructs that are similar in almost all characteristics, including cytotoxicity, to wild-type Aβ42. Conversely, the cis-AMPP Aβ42 congeners formed nonfibrillar, amorphous aggregates that exhibited no cytotoxicity. Additionally, cis-trans photoisomerization resulted in rapid formation of native-like amyloid fibrils and trans−cis conversion in the fibril state reduced the population of native-like fibrils. Thus, temporal photocontrol over Aβ turn conformation provides significant insight into Aβ self-assembly. Specifically, Aβ mutants that adopt stable β-turns form aggregate structures that are unable to enter folding pathways leading to cross-β fibrils and cytotoxic prefibrillar intermediates.

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Section: ■ Results and Discussionmentioning

confidence: 99%

An Azobenzene Photoswitch Sheds Light on Turn Nucleation in Amyloid-β Self-Assembly

Doran

Anderson

Latchney

et al. 2012

ACS Chem. Neurosci.

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“…6, 10 To reliably access glucagon‐like peptide‐1 receptor (GLP‐1R) photoactivation through geometric alterations to ligand structure, an azobenzene photoswitch comprising the amino acid [3‐(3‐aminomethyl)phenylazo]phenylacetic acid (AMPP)9b, 11 was incorporated into liraglutide. To minimize disruption to helix folding, AMPP was inserted as a bridge between the two α‐helices of liraglutide (PDB ID: 4apd; Figure 1 a), replacing amino acids 22 G‐ 23 Q, to obtain LirAzo by solid‐phase peptide synthesis (Figure 1 c and Table S1 in the Supporting Information).…”

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confidence: 99%

Optical Control of Insulin Secretion Using an Incretin Switch

et al. 2015

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Incretin mimetics are set to become a mainstay of type 2 diabetes treatment. By acting on the pancreas and brain, they potentiate insulin secretion and induce weight loss to preserve normoglycemia. Despite this, incretin therapy has been associated with off‐target effects, including nausea and gastrointestinal disturbance. A novel photoswitchable incretin mimetic based upon the specific glucagon‐like peptide‐1 receptor (GLP‐1R) agonist liraglutide was designed, synthesized, and tested. This peptidic compound, termed LirAzo, possesses an azobenzene photoresponsive element, affording isomer‐biased GLP‐1R signaling as a result of differential activation of second messenger pathways in response to light. While the trans isomer primarily engages calcium influx, the cis isomer favors cAMP generation. LirAzo thus allows optical control of insulin secretion and cell survival.

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“…We and others (8)(9)(10) have recently focused on the design of photocontrolled ␤-hairpin peptides. To enable an ultrafast initiation of ␤-hairpin folding and unfolding the azobenzene derivative 3-(3-aminomethylphenylazo)phenylacetic acid (AMPP) was used as a reversible light switch (8,10), which, in the cis isomeric state, acts as ␤-turn mimetic (see Fig. 1A).…”

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confidence: 99%

Light-triggered β-hairpin folding and unfolding

Schrader

Schreier

Cordes

et al. 2007

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

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A light-switchable peptide is transformed with ultrashort pulses from a ␤-hairpin to an unfolded hydrophobic cluster and vice versa. The structural changes are monitored by mid-IR probing. Instantaneous normal mode analysis with a Hamiltonian combining density functional theory with molecular mechanics is used to interpret the absorption transients. Illumination of the ␤-hairpin state triggers an unfolding reaction that visits several intermediates and reaches the unfolded state within a few nanoseconds. In this unfolding reaction to the equilibrium hydrophobic cluster conformation, the system does not meet significant barriers on the free-energy surface. The reverse folding process takes much longer because it occurs on the time scale of 30 s. The folded state has a defined structure, and its formation requires an extended search for the correct hydrogen-bond pattern of the ␤-strand.density functional theory calculation ͉ peptide folding ͉ TrpZip2 ͉ ultrafast infrared spectroscopy F olding is a key process during the formation of a functional protein after the synthesis of its amino acid chain (1). During folding, the amino acid chains are rearranged in highly complex processes, for which a detailed understanding is still missing. Straightforward solutions of the folding problem are prevented by the high dimensionality of the protein conformational spaces and by the wide range of relevant time scales. Thus, for complexity reduction, one has to focus on typical protein substructures, which are small enough to be analyzed by present-day technology. With corresponding peptide model systems there is a chance to monitor the formation of secondary structures, to identify characteristic intermediate states of these folding dynamics, and to carry out realistic simulations on a molecular level. An interesting class of model systems are light-triggered peptides, within which the incorporation of a photoresponsive element can initiate structural changes.Among corresponding photoresponsive chromophores, azobenzene derivatives have become a popular choice when it comes to selecting a fast conformational trigger for peptide refolding, because their structure significantly changes on time scales of a few hundred femtoseconds after photoexcitation. Indeed, an azobenzene chromophore, used as a backbone element within cyclic peptides, was shown to induce large-scale conformational changes, whose dynamics could be monitored by visible (2) and IR (3) spectroscopy. Moreover, the experimental results clearly showed that the initial, strongly driven conformational changes of the peptide proceeded within a few picoseconds after the trigger event. Externally linked to an ␣-helix, azobenzene also was used for unfolding (4) and refolding (5) of an ␣-helical model peptide in the nanosecond to microsecond time range.A prominent secondary structure motif is the ␤-sheet, for which a ␤-hairpin represents a minimal model (6, 7). We and others (8-10) have recently focused on the design of photocontrolled ␤-hairpin peptides. To enable an ultrafa...

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A Photoinducible β-Hairpin

Cited by 129 publications

References 52 publications

An Azobenzene Photoswitch Sheds Light on Turn Nucleation in Amyloid-β Self-Assembly

An Azobenzene Photoswitch Sheds Light on Turn Nucleation in Amyloid-β Self-Assembly

Optical Control of Insulin Secretion Using an Incretin Switch

Light-triggered β-hairpin folding and unfolding

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