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Carlier L.,CNRS Biomolecules Laboratory | Byrne C.,CNRS Biomolecules Laboratory | Miclet E.,CNRS Biomolecules Laboratory | Bourgoin-Voillard S.,CNRS Paris Institute of Molecular Chemistry | And 9 more authors.
Biochemical and Biophysical Research Communications | Year: 2012

The transcriptional activity of human estrogen receptor ERα is modulated by a number of coregulatory proteins among which calmodulin (CaM). Segment 295-311 in the hinge region of ERα has previously been proposed to be the CaM binding site. In this work, we investigate the molecular mechanism of the interaction of CaM with peptides derived from the hinge region of ERα, using a biophysical approach combining isothermal titration calorimetry, fluorescence, CD and NMR. The ERα17p peptide, corresponding to the previously identified 295-311 region of ERα, recruits mainly the C-terminal domain of Ca4CaM, as shown by NMR spectroscopy. In contrast, a longer peptide, ERα25p, extended on the N-terminal side (residues 287-311) interacts with both N- and C-terminal domains of Ca4CaM. These results lead to a new delineation of the CaM binding site, encompassing residues 287-294. In particular, fluorescence spectroscopy reveals that the conserved W292 residue is engaged within hydrophobic pockets on Ca4CaM. ITC results show that ERα25p binds Ca4CaM with an atypical 2:1 stoichiometry and a dissociation constant in the micromolar range. Based on the NMR titration of Ca4CaM by ERα25p showing a biphasic behavior for several residues, we suggest that concerted conformational changes of CaM domains may be required to accommodate the binding of a second peptide. CD spectra indicate that ERα25p partially folds into an α-helix upon binding to Ca4CaM. Hence, ERα25p is a new CaM-binding ligand that could be appropriate for the synthesis of derivatives able to control ER-dependent transcription, particularly in the context of hormone-dependent breast tumors. © 2012 Elsevier Inc.

Byrne C.,CNRS Biomolecules Laboratory | Khemtemourian L.,CNRS Biomolecules Laboratory | Pelekanou V.,University of Crete | Kampa M.,University of Crete | And 6 more authors.
Steroids | Year: 2012

Recently, we identified a peptide (ERα17p, P 295LMIKRSKKNSLALSLT311) that corresponds to the 295-311 sequence of the estrogen receptor α (ERα, hinge region) and which exerts a panel of pharmacological effects in breast cancer cells. Remarkably, these effects can result from the interaction of ERα17p with the plasma membrane. Herein, we show that ERα17p adopts a β-sheet secondary structure when in contact with anionic phospholipids and that it is engulfed within the lipid bilayer. While ERα17p increases the fluidity of membrane mimics, it weakly internalizes in living cells. In light of the above, one may evoke one important role of the 295-311 region of the ERα: the corresponding peptide could be secreted/delivered to the extracellular medium to interact with neighboring cells, both intracellularly and at the membrane level. Finally, the 295-311 region of ERα being in proximity to the cystein-447, the palmitoylation site of the ERα raises the question of its involvement in the interaction/stabilization of the protein with the membrane. © 2011 Elsevier Inc. All rights reserved.

Agency: Cordis | Branch: FP7 | Program: ERC-SG | Phase: ERC-SG-LS5 | Award Amount: 1.50M | Year: 2011

More than a century after Wernicke and Broca established that speech perception and production rely on temporal and prefrontal cortices of the left brain hemisphere, the biological determinants for this organization are still unknown. While functional neuroanatomy has been described in great detail, the neuroscience of language still lacks a physiologically plausible model of the neuro-computational mechanisms for coding and decoding of speech acoustic signal. We propose to fill this gap by testing the biological validity and exploring the computational implications of one promising proposal, the Asymmetric Sampling in Time theory. AST assumes that speech signals are analysed in parallel at multiple timescales and that these timescales differ between left and right cerebral hemispheres. This theory is original and provocative as it implies that a single computational difference, distinct integration windows in right and left auditory cortices could be sufficient to explain why speech is preferentially processed by the left brain, and possible even why the human brain has evolved toward such an asymmetric functional organization. Our proposal has four goals: 1/ to validate, invalidate or amend AST on the basis of physiological experiments in healthy human subjects including functional magnetic resonance imaging (fMRI), combined electroencephalography (EEG) and fMRI, magnetoencephalography (MEG) and subdural electrocorticography (EcoG), 2/ to use computational modeling to probe those aspects of the theory that currently remain inaccessible to empirical testing (evaluation, assessment), 3/ to apply AST to binaural artificial hearing with cochlear implants, 4/ to test for disorders of auditory sampling in autism and dyslexia, two language neurodevelopmental pathologies in which a genetic basis implicates the physiological underpinnings of AST, and 5/ to assess potential generalisation of AST to linguistic action in the context of speech production.

Agency: Cordis | Branch: FP7 | Program: ERC-AG | Phase: ERC-AG-SH4 | Award Amount: 2.36M | Year: 2011

The present project aims to provide a naturalistic account of epistemic norms, and of the associated epistemic awareness in children and adults from different cultures. Epistemics norms (ENs) such as intelligibility, relevance, truth, coherence and consensus are dimensions on which mental contents can be evaluated for their contribution to knowledge acquisition. Although EN sensitivity is central in education, little is known about 1) how to systematically analyze and inventory ENs, nor about 2) How and to what extent, children and adults from different cultures and socioeconomic backgrounds recognize them in making epistemic decisions. Specialists in philosophy of mind, developmental and adult congitive science, along with field anthropology, will apply their methods to address these questions in an interdisciplinary spirit. A common methodological guideline will be to study EN sensitivity as embedded in self-evaluative judgments, and to focus on cases of conflict between various ENs, such as consensus versus truth. This research should reveal how EN sensitivity develops in European and Japanese children, what role is to be assigned, in norm dominance, to emotional interaction, epistemic or social deference, and how EN sensitivity is transferred, in similar tasks and contexts, from self to others and reciprocally.

Jacquot Y.,University of Franche Comte | Jacquot Y.,Ecole Normale Superieure de Paris | Byrne C.,Ecole Normale Superieure de Paris | Xicluna A.,University of Franche Comte | And 2 more authors.
Medicinal Chemistry Research | Year: 2013

Molecules with potent estrogenic activity are ~270 Å3 hydrophobic structures that encompass two hydroxyls among which is at least one phenol. However, compounds with only one phenol or devoid of such a ring have been shown to enhance ERα-mediated transcription at concentrations much larger than those measured with E2. In this context, we show here that benzopyrans sharing one hydroxyl/methoxyl and containing an additional benzylidenyl or a spirocyclohexyl motif are able to induce ERE-dependent transcription in breast carcinoma cells. © 2012 Springer Science+Business Media, LLC.

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