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Nardi, F. De; Kemmink, Johan; Sattler, Michael; Wade, Rebecca C.

doi:10.1023/a:1008380807603

Cited by 26 publications

(25 citation statements)

References 38 publications

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“…Evidently, Pro-35 and most probably Pro-14 are the residues possessing the highest cis-content. According to studies on different proteins, this might arises from interactions with adjacent aromatic residues (76). Two aromatic residues are located distal and proximal to the N-terminal helix.…”

Section: Discussionmentioning

confidence: 99%

Structural Characterization of the HIV-1 Vpr N Terminus

Bruns

Fossen

Wray

et al. 2003

Journal of Biological Chemistry

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The 96-residue human immunodeficiency virus (HIV) accessory protein Vpr serves manifold functions in the retroviral life cycle including augmentation of viral replication in non-dividing host cells, induction of G 2 cell cycle arrest, and modulation of HIV-induced apoptosis. Using a combination of dynamic light scattering, circular dichroism, and NMR spectroscopy the N terminus of Vpr is shown to be a unique domain of the molecule that behaves differently from the C-terminal domain in terms of self-association and secondary structure folding. Interestingly, the four highly conserved proline residues in the N terminus are predicted to have a high propensity for cis/trans isomerism. Thus the high resolution structure and folding of a synthetic N-terminal peptide (Vpr 1-40 ) and smaller fragments thereof have been investigated. 1 H NMR data indicate Vpr 1-40 possesses helical structure between residues 17-32, and for the first time, this helix, which is bound by proline residues, was observed even in aqueous solution devoid of any detergent supplements. In addition, NMR data revealed that all of the proline residues undergo a cis/ trans isomerism to such an extent that ϳ40% of all Vpr molecules possess at least one proline in a cis conformation. This phenomenon of cis/trans isomerism, which is unprecedented for HIV-1 Vpr, not only provides an explanation for the molecular heterogeneity observed in the full-length molecule but also indicates that in vivo the folding and function of Vpr should depend on a cis/trans-proline isomerase activity, particularly as two of the proline residues in positions 14 and 35 show considerable amounts of cis isomers. This prediction correlates well with our recent observation

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Section: Discussionmentioning

confidence: 99%

Structural Characterization of the HIV-1 Vpr N Terminus

Bruns

Fossen

Wray

et al. 2003

Journal of Biological Chemistry

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“…The s ring value is influenced by the proximity and orientation of the aromatic ring. Interacting groups with s ring of À0.25 ppm or lower are considered to contain CHÁ Á Áp interactions [29,30]. The Total program [31] was used to calculate s ring .…”

Section: Methodsmentioning

confidence: 99%

Flap opening mechanism of HIV-1 protease

Tóth¹,

Borics

2006

Journal of Molecular Graphics and Modelling

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“…12 Similarly, Pro-Aromatic sequences also exhibit an increased propensity for cis-Pro amide bonds, especially when preceded by an additional aromatic or proline residue. 7–11,20–23 …”

Section: Introductionmentioning

confidence: 99%

Aromatic–Proline Interactions: Electronically Tunable CH/π Interactions

2012

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CONSPECTUS Proline residues have unique roles in protein folding, structure, and function. Proline combined with the aromatic amino acids comprise the encoded cyclic protein residues. Aromatic protein side chains are defined by their negatively charged π faces, while the faces of the proline ring are partially positively charged. This polarity results from their two-point connection of the side chain to the electron-withdrawing protein backbone, and the lower electronegativity of hydrogen compared to carbon, nitrogen, and oxygen. The hydrogens adjacent to the carbonyl and amide nitrogen, Ha and Hδ, respectively, are the most partially positive. Proline’s side chain is also conformationally restricted, allowing for interaction with aromatic residues with minimal entropic or steric penalty. Proline and aromatic residues can interact favorably with each other, due to both the hydrophobic effect and the interaction between the π aromatic face and the polarized C-H bonds, called a CH/π interaction. Aromatic-proline interactions can occur locally, for example to stabilize cis-amide bonds, and over larger distances, in the tertiary structures of proteins, and intermolecularly in protein-protein interactions. In peptides and proteins, aromatic-proline sequences more readily adopt cis-prolyl amide bonds, where the aromatic ring interacts with the proline ring in the cis conformation. In aromatic-proline sequences, Trp and Tyr are more likely to induce cis-amide bonds than Phe, suggesting an aromatic electronic effect. This result would be expected for a CH/π interaction, in which a more electron-rich aromatic would have a stronger (more cis-stabilizing) interaction with partial positive charges on prolyl hydrogens. In this Account, we describe our investigations into the nature of local aromatic-proline interactions, using peptide models. We synthesized a series of 26 peptides, TXPN, varying X from electron-rich to electron poor aromatic amino acids, and found that the population of cis-amide bond (Ktrans/cis) is tunable by aromatic electronics. With 4-substituted phenylalanines, we observed a Hammett correlation between aromatic electronics and Ktrans/cis, with cis-trans isomerism electronically controllable by 1.0 kcal/mol. All aromatic residues exhibit a higher cis population than Ala or cyclohexylalanine, with Trp showing the strongest aromatic-proline interaction. In addition, proline stereoelectronic effects can modulate cis-trans isomerism by an additional 1.0 kcal/mol. The aromatic-proline interaction is enthalpic, consistent with its description as a CH/π interaction. Proline-aromatic sequences can also promote cis-prolyl bonds, either through interactions of the aromatic ring with the preceding cis-proline, or with the Hα prior to cis-proline. Within proline-rich peptides, sequences commonly found in natively disordered proteins, aromatic residues promote multiple cis-amide bonds due to multiple favorable aromatic-proline interactions. Collectively, we found aromatic-proline interactions to be significantly CH/...

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Untitled

Cited by 26 publications

References 38 publications

Structural Characterization of the HIV-1 Vpr N Terminus

Structural Characterization of the HIV-1 Vpr N Terminus

Flap opening mechanism of HIV-1 protease

Aromatic–Proline Interactions: Electronically Tunable CH/π Interactions

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