New factors enhancing the reactivity of cysteines in molten globule-like structures

Protein cysteines often play crucial functional and structural roles, so they are emerging targets to design covalent thiol ligands that are able to modulate enzyme or protein functions. Some of these residues, especially those involved in enzyme mechanisms-including nucleophilic and reductive catalysis and thiol-disulfide exchange-display unusual hyper-reactivity; such a property is expected to result from a low pK(a)and from a great accessibility to a given reagent. New findings and previous evidence clearly indicate that pK(a)perturbations can only produce two-four-times increased reactivity at physiological pH values, far from the hundred and even thousand-times kinetic enhancements observed for some protein cysteines. The data from the molten globule-like structures of ribonuclease, lysozyme, bovine serum albumin and chymotrypsinogen identified new speeding agents, i.e., hydrophobic/electrostatic interactions and productive complex formations involving the protein and thiol reagent, which were able to confer exceptional reactivity to structural cysteines which were only intended to form disulfides. This study, for the first time, evaluates quantitatively the different contributions of pK(a)and other factors to the overall reactivity. These findings may help to clarify the mechanisms that allow a rapid disulfide formation during the oxidative folding of many proteins

Ultra-rapid glutathionylation of chymotrypsinogen in its molten globule-like conformation: a comparison to archaeal proteins

Chymotrypsinogen, when reduced and taken to its molten globule-like conformation, displays a single cysteine with an unusual kinetic propensity toward oxidized glutathione (GSSG) and other organic thiol reagents. A single residue, identified by mass spectrometry like Cys1, reacts with GSSG about 1400 times faster than an unperturbed protein cysteine. A reversible protein-GSSG complex and a low pK(a) (8.1 +/- 0.1) make possible such astonishing kinetic property which is absent toward other natural disulfides like cystine, homocystine and cystamine. An evident hyper-reactivity toward 5,5 ' -dithiobis-(2-nitrobenzoic acid) (DTNB) and 1-chloro-2,4-dinitrobenzene (CDNB) was also found for this specific residue. The extraordinary reactivity toward GSSG is absent in two proteins of the thermophilic archaeon Sulfolobus solfataricus, an organism lacking glutathione: the Protein Disulphide Oxidoreductase (SsPDO) and the Bacterioferritin Comigratory Protein 1 (Bcp1) that displays Cys residues with an even lower pK(a) value (7.5 +/- 0.1) compared to chymotrypsinogen. This study, which also uses single mutants in Cys residues for Bcp1, proposes that this hyper-reactivity of a single cysteine, similar to that found in serum albumin, lysozyme, ribonuclease, may have relevance to drive the "incipit" of the oxidative folding of proteins from organisms where the glutathione/oxidized glutathione (GSH/GSSG) system is present

Multi-criterion trade-offs and synergies for spatial conservation planning

1. Nature conservation policies need to deliver on multiple criteria, including genetic diversity, population viability and species richness as well as ecosystem services. The challenge of integrating these may be addressed by simulation modelling. 2. We used four models (MetaConnect, SPOMSIM, a community model and InVEST) to assess a variety of spatial habitat patterns with two levels of total habitat cover and realised at two spatial scales, exploring which landscape structures performed best according to five different criteria assessed for four functional types of organisms (approximately representing trees, butterflies, small mammals and birds). 3. The results display both synergies and trade-offs: population size and pollination services generally benefitted more from fragmentation than did genetic heterozygosity, and species richness more than allelic richness, although the latter two varied considerably among the functional types. 4. No single landscape performed best across all criteria, but averaging over criteria and functional types, overall performance improved with greater levels of habitat cover and intermediate fragmentation (or less fragmentation in cases with lower habitat cover). 5. Synthesis and applications. Different conservation objectives must be traded off, and considering only a single taxon or criterion may result in sub-optimal choices when planning reserve networks. Nevertheless, heterogeneous spatial patterns of habitat can provide reasonable compromises for multiple criteria

Dispersal Evolution in Currents : spatial sorting promotes philopatry in upstream patches

Open Access via the Wiley Jisc Agreeement Funding – This work was funded by MarCRef, a collaboration between the Univ. of Aberdeen [grant number CF10434‐53] and Marine Scotland [grant number RG14645‐10], as part of Rebekka Allgayer's PhD program and Research Councils UK, Natural Environment Research Council, NE/T006935/1. The code for the model is available in a GitHub repository: .Peer reviewedPublisher PD

Ebolavirus and Marburgvirus: insight the Filoviridae family

Ebolavirus and Marburgvirus (belonging to the Filoviridae family) emerged four decades ago and cause epidemics of haemorrhagic fever with high case-fatality rates. The genome of filoviruses encodes seven proteins. No significant homology is observed between filovirus proteins and any known macromolecule. Moreover, Marburgvirus and Ebolavirus show significant differences in protein homology. The natural maintenance cycle of filoviruses is unknown, the natural reservoir, the mode of transmission, the epidemic disease generation, and temporal dynamics are unclear. Lastly, Ebolavirus and Marburgvirus are considered as potential biological weapons. Vaccine appears the unique therapeutic frontier. Here, molecular and clinical aspects of filoviral haemorrhagic fevers are summarized

Targeting oncogenic Src homology 2 domain-containing phosphatase 2 (SHP2) by inhibiting its protein-protein interactions

We developed a new class of inhibitors of protein-protein interactions of the SHP2 phosphatase, which is pivotal in cell signaling and represents a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective for disease-associated SHP2 mutants. Considering that pathogenic lesions cause signaling hyperactivation due to increased levels of SHP2 association with cognate proteins, we developed peptide-based molecules with nanomolar affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation, and an affinity for pathogenic variants of SHP2 that is 2-20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant (D61G) in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool for investigating the role of protein-protein interactions in the function of SHP2

Evolution of predator dispersal in relation to spatio-temporal prey dynamics : how not to get stuck in the wrong place!

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Improving the forecast for biodiversity under climate change

Acknowledgments: This paper originates from the “Ecological Interactions and Range Evolution Under Environmental Change” and “RangeShifter” working groups, supported by the Synthesis Centre of the German Centre for Integrative Biodiversity Research (DFG-FZT-118), DIVERSITAS, and its core projects bioDISCOVERY and bioGENESIS. Supported by the Canada Research Chair, Natural Sciences and Engineering Research Council of Canada, and Quebec Centre for Biodiversity Science (A.G.); the University of Florida Foundation (R.D.H.); KU Leuven Research Fund grant PF/2010/07, ERA-Net BiodivERsA TIPPINGPOND, and Belspo IAP SPEEDY (L.D.M.); European Union Biodiversity Observation Network grant EU-BON-FP7-308454 (J.-B.M. and G.P.); KU Leuven Research Fund (J.P.); and NSF grants DEB-1119877 and PLR-1417754 and the McDonnell Foundation (M.C.U.).Peer reviewedPostprin

Fauxcurrence: simulating multi-species occurrences for null models in species distribution modelling and biogeography

The work was funded by Newton Fund (UK)/NERC (UK)/RISTEKDIKTI (Indonesia) grants awarded to JT, BJ, ACA, ASTP, CG-R, GB and LTL (grant no.: NE/S006923/1, NE/S006893/1, 2488/IT3.L1/PN/2020 and 3982/IT3.L1/PN/2020). GB and CG-R are funded by Royal Society Univ. Research Fellowships (UF160614 and UF150571 respectively).Peer reviewedPublisher PD