Does tetracycline bind helix 2 of prion? An integrated spectroscopical and computational study of the interaction between the antibiotic and α helix 2 human prion protein fragments

Ronga, Luisa; Langella, Emma; Palladino, Pasquale; Marasco, Daniela; Tizzano, Barbara; Pedone, Carlo; Improta, Roberto; Ruvo, Menotti

doi:10.1002/prot.21204

Cited by 28 publications

(19 citation statements)

References 39 publications

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“…To develop more effective anti-prion pharmacological approaches, a wide number of molecules have been screened for their ability to counteract biochemical and biological properties of PrP Sc (Trevitt and Collinge 2006). Among others known drugs, tetracyclines were reported to significantly affect both in vivo (Forloni et al 2002;De Luigi et al 2008) and in vitro PrP Sc toxicity, interfering with prion resistance to PK , via a direct binding to lipophilic domains of the protein (Ronga et al 2007). Similar results were also obtained when a pretreatment with tetracyclines was performed in experimental models of prion-induced neurotoxicity and gliosis using other PrP-derived peptides .…”

Section: Discussionmentioning

confidence: 99%

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Dual Modulation of ERK1/2 and p38 MAP Kinase Activities Induced by Minocycline Reverses the Neurotoxic Effects of the Prion Protein Fragment 90–231

et al. 2009

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Several in vitro and in vivo studies addressed the identification of molecular determinants of the neuronal death induced by PrP(Sc) or related peptides. We developed an experimental model to assess PrP(Sc) neurotoxicity using a recombinant polypeptide encompassing amino acids 90-231 of human PrP (hPrP90-231) that corresponds to the protease-resistant core of PrP(Sc) identified in prion-infected brains. By means of mild thermal denaturation, we can convert hPrP90-231 from a PrP(C)-like conformation into a PrP(Sc)-like structure. In virtue of these structural changes, hPrP90-231 powerfully affected the survival of SH-SY5Y cells, inducing caspase 3 and p38-dependent apoptosis, while in the native alpha-helix-rich conformation, hPrP90-231 did not induce cell toxicity. The aim of this study was to identify drugs able to block hPrP90-231 neurotoxic effects, focusing on minocycline, a tetracycline with known neuroprotective activity. hPrP90-231 caused a caspase 3-dependent apoptosis via the blockade of ERK1/2 activation and the subsequent activation of p38 MAP kinase. We propose that hPrP90-231-induced apoptosis is dependent on the inhibition of ERK1/2 responsiveness to neurotrophic factors, removing a tonic inhibition of p38 activity and resulting in caspase 3 activation. Minocycline prevented hPrP90-231-induced toxicity interfering with this mechanism: the pretreatment with this tetracycline restored ERK1/2 activity and reverted p38 and caspase 3 activities. The effects of minocycline were not mediated by the prevention of hPrP90-231 structural changes or cell internalization (differently from Congo Red). In conclusion, minocycline elicits anti-apoptotic effects against the neurotoxic activity of hPrP90-231 and these effects are mediated by opposite modulation of ERK1/2 and p38 MAP kinase activities.

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Section: Discussionmentioning

confidence: 99%

“…Tetracyclines are known to bind to PrP fragments Ronga et al 2007). To investigate the mechanisms underlying the neuro-protection exerted by minocycline, we evaluated its binding affinity to hPrP90-231.…”

Section: Interactions Of Minocycline With Hprp90-231mentioning

confidence: 99%

Dual Modulation of ERK1/2 and p38 MAP Kinase Activities Induced by Minocycline Reverses the Neurotoxic Effects of the Prion Protein Fragment 90–231

et al. 2009

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“…A fully atomistic molecular dynamics of the whole chicken prion protein, ChPrP1-267, was carried out in water at neutral pH. In these conditions, available pK values [31] indicate that the ionizable amino acids such as histidines (41,54,60,66,72,84,104,118,147,247,267, protonated at the d nitrogen) and tyrosines (46,52,58,64,70,76,82,88,95,103,135,146,154,164,169,170,173,194,235,238) are in the neutral state; glutamic (153,159,193,206,215,217,219,229,237) and aspartic (20,149,152,172,180,185,250) acids are negatively charged, while lysines (25,26,28,30,107,110,113,117,…”

Section: Simulation Detailsmentioning

confidence: 99%

Conformational Preferences of the Full Chicken Prion Protein in Solution and Its Differences with Respect to Mammals

et al. 2009

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We investigate the conformations of the full chicken prion protein (ChPrP1-267) in solution at neutral pH with molecular dynamics simulations. We focus on the persistence of its secondary structure motifs using a recently proposed protein chirality indicator [A. Pietropaolo et al., Proteins 2008, 70, 667-677]. From this, we find a high rigidity of helix 2 (ChPrP178-195) and of the hexarepeat domain, which is turn rich, and a plasticity of the short beta-sheet, consistent with the available NMR structural details. We also determine the extent of solvation for each residue, revealing local minima for such structured regions. These features hint at a possible origin of the high resistance to proteolysis of the avian prion proteins and of its capability in preventing the aggregation in comparison to mammals.

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“…A thermodynamic study of the α-helix 2 peptide showed that the free energy separating the α-helix and β-sheet conformations of this peptide is very small, indicating that the structural behavior of this peptide is likely determined by the environment29. Indeed, compounds binding to this region have been shown to prevent PrP conversion and increase the survival of diseased animals303132.…”

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confidence: 99%

The role of the unusual threonine string in the conversion of prion protein

Abskharon

Wang

Stel

et al. 2016

Sci Rep

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The conversion of normal prion protein (PrP) into pathogenic PrP conformers is central to prion disease, but the mechanism remains unclear. The α-helix 2 of PrP contains a string of four threonines, which is unusual due to the high propensity of threonine to form β-sheets. This structural feature was proposed as the basis for initiating PrP conversion, but experimental results have been conflicting. We studied the role of the threonine string on PrP conversion by analyzing mouse Prnpa and Prnpb polymorphism that contains a polymorphic residue at the beginning of the threonine string, and PrP mutants in which threonine 191 was replaced by valine, alanine, or proline. The PMCA (protein misfolding cyclic amplification) assay was able to recapitulate the in vivo transmission barrier between PrPa and PrPb. Relative to PMCA, the amyloid fibril growth assay is less restrictive, but it did reflect certain properties of in vivo prion transmission. Our results suggest a plausible theory explaining the apparently contradictory results in the role of the threonine string in PrP conversion and provide novel insights into the complicated relationship among PrP stability, seeded conformational change, and prion structure, which is critical for understanding the molecular basis of prion infectivity.

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Does tetracycline bind helix 2 of prion? An integrated spectroscopical and computational study of the interaction between the antibiotic and α helix 2 human prion protein fragments

Cited by 28 publications

References 39 publications

Dual Modulation of ERK1/2 and p38 MAP Kinase Activities Induced by Minocycline Reverses the Neurotoxic Effects of the Prion Protein Fragment 90–231

Dual Modulation of ERK1/2 and p38 MAP Kinase Activities Induced by Minocycline Reverses the Neurotoxic Effects of the Prion Protein Fragment 90–231

Conformational Preferences of the Full Chicken Prion Protein in Solution and Its Differences with Respect to Mammals

The role of the unusual threonine string in the conversion of prion protein

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