Late Variscan plutonic bodies are widespread in the External Crystalline Massifs of the Alps (Argentera, Pelvoux, Belledonne, Grandes Rousses, Mont Blanc, Aiguilles Rouges, Aar, Gotthard). They can be classified on the basis of their Mg/(Fe + Mg) ratio and mafic mineral content (expressed by the B = Fe + Mg + Ti parameter). Together with available ages of emplacement, this classification highlights the existence of two plutonic suites, one early, Viséan (∼330–340 Ma), and highly magnesian, the other later, mainly Stephanian (∼295–305 Ma), and more ferriferous. This evolution from a magnesian plutonism to a more ferriferous one, which also occurs in other Variscan massifs (e.g. Corsica), might be accounted for by a combination of factors related to the nature of the source of the magmas, the physical and chemical conditions of melting, and the Late Variscan geodynamic setting. As a basis for these considerations a comprehensive review is presented of all the External Crystalline Massifs and theirLate Variscan intrusions.
Abstract The hepatitis C virus (HCV) viroporin p7 oligomerizes to form ion channels, which are required for the assembly and secretion of infectious viruses. The 63-amino acid p7 monomer has two putative transmembrane domains connected by a cytosolic loop, and has both N- and C- termini exposed to the endoplasmic reticulum (ER) lumen. NMR studies have indicated differences between p7 structures of distantly related HCV genotypes. A critical question is whether these differences arise from the high sequence variation between the different isolates and if so, how the divergent structures can support similar biological functions. Here, we present a side-by-side characterization of p7 derived from genotype 1b (isolate J4) in the detergent 6-cyclohexyl-1-hexylphosphocholine (Cyclofos-6) and p7 derived from genotype 5a (isolate EUH1480) in n -dodecylphosphocholine (DPC). The 5a isolate p7 in conditions previously associated with a disputed oligomeric form exhibits secondary structure, dynamics, and solvent accessibility broadly like those of the monomeric 1b isolate p7. The largest differences occur at the start of the second transmembrane domain, which is destabilized in the 5a isolate. The results show a broad consensus among the p7 variants that have been studied under a range of different conditions and indicate that distantly related HCVs preserve key features of structure and dynamics.
Abstract Perforin-2 (PFN2, MPEG1) is a pore-forming protein that acts as a first line of defense in the mammalian immune system, rapidly killing engulfed microbes within the phagolysosome in macrophages. PFN2 self-assembles into hexadecameric pre-pore rings that transition upon acidification into pores damaging target cell membranes. Here, using high-speed atomic force microscopy (HS-AFM) imaging and line-scanning and molecular dynamics simulation, we elucidate PFN2 pre-pore to pore transition pathways and dynamics. Upon acidification, the pre-pore rings (pre-pore-I) display frequent, 1.8 s −1 , ring-opening dynamics that eventually, 0.2 s −1 , initiate transition into an intermediate, short-lived, ~75 ms, pre-pore-II state, inducing a clockwise pre-pore-I to pre-pore-II propagation. Concomitantly, the first pre-pore-II subunit, undergoes a major conformational change to the pore state that propagates also clockwise at a rate ~15 s −1 . Thus, the pre-pore to pore transition is a clockwise hand-over-hand mechanism that is accomplished within ~1.3 s. Our findings suggest a clockwise mechanism of membrane insertion that with variations may be general for the MACPF/CDC superfamily.
La reconstitution de series climatiques historiques suscite ces dernieres annees un interet croissant, qu'il s'agisse d'etudier la variabilite des climats du passe, de positionner le changement climatique dans le long terme, ou encore d'ameliorer la connaissance des episodes extremes dans le cadre de la prevention des risques naturels. Dans le cadre d'une recherche sur les extremes hydrologiques de la Meuse et de la Moselle (projet RECRET), nous avons realise des reconstitutions de longues series climatiques (Delus et al., 2018) qui seront utilisees pour alimenter un modele pluie-debit afin de simuler des series de debits historiques. Les reconstitutions climatiques reposent sur une base de donnees climatologique inedite. Cette base de donnees a ete utilisee pour elaborer des grilles spatialisees a partir desquelles sont etablies des series de precipitations et de temperatures moyennes de bassins versants depuis janvier 1860. Les donnees climatologiques historiques peuvent etre affectees de biais lies a des changements d'instrumentation, d'observateur ou encore de localisation de poste. De plus, ces donnees sont souvent discontinues, ce qui ne permet pas de procedure d'homogeneisation et de critique des donnees. La validite des series climatiques est donc difficile a etablir. Pour permettre une evaluation relative des series, nous proposons de comparer les series reconstituees a des reconstructions climatiques issues de differents travaux : (i) SCOPE Climate, qui propose a l'echelle de la France des reconstructions de precipitations et de temperatures journalieres sur une grille de 8 km depuis 1871 a partir d'informations sur la circulation atmospherique (Caillouet et al., 2016, 2017) ; (ii) FYRE Climate, qui integre les observations historiques au sol dans les reconstructions SCOPE Climate par un processus d'assimilation de donnees (Devers et al., 2018) ; (iii) une reconstruction des precipitations et temperatures mensuelles de bassin sur la periode 1659-2017, elaboree a partir des champs de pression atmospherique et en altitude, sur la base des travaux de Grelier (2017) ; (iv) la base de donnees E-OBS 17.0 hebergee sur le site European Climate Assessment & Dataset qui propose des donnees de precipitations et temperatures journalieres spatialisees selon une grille de resolution de 0.25° sur la periode 1950-2017 (Haylock et al., 2008) ; (v) la reanalyse de surface Safran disponible sur une grille de 8 km sur la France Metropolitaine depuis 1958 (Vidal et al., 2010). En l'absence de serie de reference, l'etude se concentrera sur la coherence entre les estimations issues de ces differentes methodes et sur une analyse de la dispersion constatee selon la profondeur des donnees. La comparaison portera plus precisement sur les series de precipitations et temperatures mensuelles moyennes sur la periode 1871-2012 de quatre sous bassins versants de la Meuse et de la Moselle (Moselle a Epinal et a Hauconcourt, Meurthe a Malzeville et Meuse a Saint-Mihiel). Le choix de ces sous-bassins est lie a la disponibilite de donnees hydrometriques historiques qui seront utilisees ulterieurement dans ce projet pour valider les reconstitutions hydro-climatologiques proposees.
Coordinated conformational transitions in oligomeric enzymatic complexes modulate function in response to substrates and play a crucial role in enzyme inhibition and activation. Caseinolytic protease (ClpP) is a tetradecameric complex, which has emerged as a drug target against multiple pathogenic bacteria. Activation of different ClpPs by inhibitors has been independently reported from drug development efforts, but no rationale for inhibitor-induced activation has been hitherto proposed. Using an integrated approach that includes x-ray crystallography, solid- and solution-state nuclear magnetic resonance, molecular dynamics simulations, and isothermal titration calorimetry, we show that the proteasome inhibitor bortezomib binds to the ClpP active-site serine, mimicking a peptide substrate, and induces a concerted allosteric activation of the complex. The bortezomib-activated conformation also exhibits a higher affinity for its cognate unfoldase ClpX. We propose a universal allosteric mechanism, where substrate binding to a single subunit locks ClpP into an active conformation optimized for chaperone association and protein processive degradation.
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