OGlcNAcylation and Phosphorylation Have Similar Structural Effects in α-Helices: Post-Translational Modifications as Inducible Start and Stop Signals in α-Helices, with Greater Structural Effects on Threonine Modification

Elbaum, Michael; Zondlo, Neal J.

doi:10.1021/bi500117c

Cited by 51 publications

(108 citation statements)

References 174 publications

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“…These results suggest that the chloroacetyl group enhances the carbonyl/carbonyl n→π* interaction through two serial n→π* interactions, whereby one n→π* interaction (here, Cl ⋅⋅⋅ C=O) makes that acceptor carbonyl a better donor for a subsequent n→π* interaction. These serial effects have been proposed to stabilize both the α‐helix and polyproline helix conformations in proteins …”

Section: Methodsmentioning

confidence: 99%

Electronic and Steric Control of n→π* Interactions: Stabilization of the α‐Helix Conformation without a Hydrogen Bond

et al. 2019

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The preferred conformations of peptides and proteins are dependent on local interactions that bias the conformational ensemble. The n→π* interaction between consecutive carbonyls promotes compact conformations, including the α‐helix and polyproline II helix. In order to further understand the n→π* interaction and to develop methods to promote defined conformational preferences through acyl N‐capping motifs, a series of peptides was synthesized in which the electronic and steric properties of the acyl group were modified. Using NMR spectroscopy, van't Hoff analysis of enthalpies, X‐ray crystallography, and computational investigations, we observed that more electron‐rich donor carbonyls (pivaloyl, iso‐butyryl, propionyl) promote stronger n→π* interactions and more compact conformations than acetyl or less electron‐rich donor carbonyls (methoxyacetyl, fluoroacetyl, formyl). X‐ray crystallography indicates a strong, electronically tunable preference for the α‐helix conformation, as observed directly on the φ and ψ torsion angles. Electron‐donating acyl groups promote the α‐helical conformation, even in the absence of the hydrogen bonding that stabilizes the α‐helix. In contrast, electron‐withdrawing acyl groups led to more extended conformations. More sterically demanding groups can promote trans amide bonds independent of the electronic effect on n→π* interactions. Chloroacetyl groups additionally promote n→π* interactions through the interaction of the chlorine lone pair with the proximal carbonyl π*. These data provide additional support for an important role of n→π* interactions in the conformational ensemble of disordered or unfolded proteins. Moreover, this work suggests that readily incorporated acyl N‐capping motifs that modulate n→π* interactions may be employed rationally to promote conformational biases in peptides, with potential applications in molecular design and medicinal chemistry.

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Section: Methodsmentioning

confidence: 99%

Electronic and Steric Control of n→π* Interactions: Stabilization of the α‐Helix Conformation without a Hydrogen Bond

et al. 2019

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“…177, 232 As such, phosphorylation, which is often viewed from a signaling point of view, has biophysical consequences that impact structural features of N17 and htt aggregation. For example, phosphorylation has a generic ability to destabilize α-helicity in proteins, 244 this has been specifically demonstrated for htt peptides. 177 Inhibited aggregation of htt due to phosphorylation in N17 could be partially attributed to destabilization of α-helical mediated self-association of N17 into tetramers, which appears to be an early step in fibril formation.…”

Section: Post-translational Modifications Impact Aggregation and Toximentioning

confidence: 99%

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

et al. 2017

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Several hereditary neurological and neuromuscular diseases are caused by an abnormal expansion of trinucleotide repeats. To date, there have been ten of these trinucleotide repeat disorders associated with an expansion of the codon CAG encoding glutamine (Q). For these polyglutamine (polyQ) diseases, there is a critical threshold length of the CAG repeat required for disease, and further expansion beyond this threshold is correlated with age of onset and symptom severity. PolyQ expansion in the translated proteins promotes their self-assembly into a variety of oligomeric and fibrillar aggregate species that accumulate into the hallmark proteinaceous inclusion bodies associated with each disease. Here, we review aggregation mechanisms of proteins with expanded polyQ-tracts, structural consequences of expanded polyQ ranging from monomers to fibrillar aggregates, the impact of protein context and post translational modifications on aggregation, and a potential role for lipids membranes in aggregation. As the pathogenic mechanisms that underlie these disorders are often classified as either a gain of toxic function or loss of normal protein function, some toxic mechanisms associated with mutant polyQ tracts will also be discussed.

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“…54−56 These peptide sequences were employed to determine the conformational preferences of these amino acids within the polyproline helix and α-helix secondary structures, both of which are widely employed in molecular recognition. Matching the conformational preferences of the amino acid to the structural context in which the amino acid may be employed (protein design in “chi space”) 57 can maximize the effectiveness of the amino acids toward defined applications.…”

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confidence: 99%

(2S,4R)- and (2S,4S)-Perfluoro-tert-butyl 4-Hydroxyproline: Two Conformationally Distinct Proline Amino Acids for Sensitive Application in ¹⁹F NMR

Tressler

Zondlo

2014

J. Org. Chem.

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(2S,4R)- and (2S,4S)-perfluoro-tert-butyl 4-hydroxyproline were synthesized (as Fmoc-, Boc-, and free amino acids) in 2–5 steps. The key step of each synthesis was a Mitsunobu reaction with perfluoro-tert-butanol, which incorporated a perfluoro-tert-butyl group, with nine chemically equivalent fluorines. Both amino acids were incorporated in model α-helical and polyproline helix peptides. Each amino acid exhibited distinct conformational preferences, with (2S,4R)-perfluoro-tert-butyl 4-hydroxyproline promoting polyproline helix. Peptides containing these amino acids were sensitively detected by 19F NMR, suggesting their use in probes and medicinal chemistry.

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OGlcNAcylation and Phosphorylation Have Similar Structural Effects in α-Helices: Post-Translational Modifications as Inducible Start and Stop Signals in α-Helices, with Greater Structural Effects on Threonine Modification

Cited by 51 publications

References 174 publications

Electronic and Steric Control of n→π* Interactions: Stabilization of the α‐Helix Conformation without a Hydrogen Bond

Electronic and Steric Control of n→π* Interactions: Stabilization of the α‐Helix Conformation without a Hydrogen Bond

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

(2S,4R)- and (2S,4S)-Perfluoro-tert-butyl 4-Hydroxyproline: Two Conformationally Distinct Proline Amino Acids for Sensitive Application in ¹⁹F NMR

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OGlcNAcylation and Phosphorylation Have Similar Structural Effects in α-Helices: Post-Translational Modifications as Inducible Start and Stop Signals in α-Helices, with Greater Structural Effects on Threonine Modification

Cited by 51 publications

References 174 publications

Electronic and Steric Control of n→π* Interactions: Stabilization of the α‐Helix Conformation without a Hydrogen Bond

Electronic and Steric Control of n→π* Interactions: Stabilization of the α‐Helix Conformation without a Hydrogen Bond

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

(2S,4R)- and (2S,4S)-Perfluoro-tert-butyl 4-Hydroxyproline: Two Conformationally Distinct Proline Amino Acids for Sensitive Application in 19F NMR

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(2S,4R)- and (2S,4S)-Perfluoro-tert-butyl 4-Hydroxyproline: Two Conformationally Distinct Proline Amino Acids for Sensitive Application in ¹⁹F NMR