Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation

Calculation of the relative metastabilities of proteins using the CHNOSZ software package

<p>Abstract</p> <p>Background</p> <p>Proteins of various compositions are required by organisms inhabiting different environments. The energetic demands for protein formation are a function of the compositions of proteins as well as geochemical variables including temperature, pressure, oxygen fugacity and pH. The purpose of this study was to explore the dependence of metastable equilibrium states of protein systems on changes in the geochemical variables.</p> <p>Results</p> <p>A software package called CHNOSZ implementing the revised Helgeson-Kirkham-Flowers (HKF) equations of state and group additivity for ionized unfolded aqueous proteins was developed. The program can be used to calculate standard molal Gibbs energies and other thermodynamic properties of reactions and to make chemical speciation and predominance diagrams that represent the metastable equilibrium distributions of proteins. The approach takes account of the chemical affinities of reactions in open systems characterized by the chemical potentials of basis species. The thermodynamic database included with the package permits application of the software to mineral and other inorganic systems as well as systems of proteins or other biomolecules.</p> <p>Conclusion</p> <p>Metastable equilibrium activity diagrams were generated for model cell-surface proteins from archaea and bacteria adapted to growth in environments that differ in temperature and chemical conditions. The predicted metastable equilibrium distributions of the proteins can be compared with the optimal growth temperatures of the organisms and with geochemical variables. The results suggest that a thermodynamic assessment of protein metastability may be useful for integrating bio- and geochemical observations.</p

Structural fuzziness of the RNA-organizing protein SERF determines a toxic gain-of-interaction

The mechanisms by which protein complexes convert from functional into pathogenic are the subject of intensive research. Here, we report how functionally unfavourable protein interactions can be induced by structural fuzziness, i.e. by persisting conformational disorder in protein complexes. We show that extreme disorder in the bound state transforms the intrinsically disordered protein SERF1a from an RNA-organizing factor into a pathogenic enhancer of alpha-synuclein (aSyn) amyloid toxicity. We demonstrate that SERF1a promotes the incorporation of RNA into nucleoli and liquid-like artificial RNA-organelles by retaining an unusually high degree of conformational disorder in the RNA-bound state. However, this type of structural fuzziness also determines an undifferentiated interaction with aSyn. RNA and aSyn both bind to one identical, positively charged site of SERF1a by an analogous electrostatic binding mode, with similar binding affinities, and without any observable disorder-to-order transition. The absence of primary or secondary structure discriminants results in SERF1a being unable to select between nucleic acid and amyloidogenic protein, leading the pro-amyloid aSyn:SERF1a interaction to prevail in the cytosol under conditions of cellular stress. We suggest that fuzzy disorder in SERF1a complexes accounts for an adverse gain-of-interaction which favours toxic binding to aSyn at the expense of non-toxic RNA binding, thereby leading to a functionally distorted and pathogenic process. Thus, structural fuzziness constitutes a direct link between extreme conformational flexibility, amyloid aggregation and the malfunctioning of RNA-associated cellular processes, three signatures of neurodegenerative proteinopathies

Structural fuzziness of the RNA-organizing protein SERF determines a toxic gain-of-interaction

The mechanisms by which protein complexes convert from functional into pathogenic are the subject of intensive research. Here, we report how functionally unfavourable protein interactions can be induced by structural fuzziness, i.e. by persisting conformational disorder in protein complexes. We show that extreme disorder in the bound state transforms the intrinsically disordered protein SERF1a from an RNA-organizing factor into a pathogenic enhancer of alpha-synuclein (aSyn) amyloid toxicity. We demonstrate that SERF1a promotes the incorporation of RNA into nucleoli and liquid-like artificial RNA-organelles by retaining an unusually high degree of conformational disorder in the RNA-bound state. However, this type of structural fuzziness also determines an undifferentiated interaction with aSyn. RNA and aSyn both bind to one identical, positively charged site of SERF1a by an analogous electrostatic binding mode, with similar binding affinities, and without any observable disorder-to-order transition. The absence of primary or secondary structure discriminants results in SERF1a being unable to select between nucleic acid and amyloidogenic protein, leading the pro-amyloid aSyn:SERF1a interaction to prevail in the cytosol under conditions of cellular stress. We suggest that fuzzy disorder in SERF1a complexes accounts for an adverse gain-of-interaction which favours toxic binding to aSyn at the expense of non-toxic RNA binding, thereby leading to a functionally distorted and pathogenic process. Thus, structural fuzziness constitutes a direct link between extreme conformational flexibility, amyloid aggregation and the malfunctioning of RNA-associated cellular processes, three signatures of neurodegenerative proteinopathies

Iberomeryx minor (Mammalia, Artiodactyla) from the Early Oligocene of Soulce (Canton Jura, NW Switzerland): systematics and palaeodiet

The primitive ruminant genus Iberomeryx is poorly documented, as it is essentially only known from rare occurrences of dental remains. Therefore, the phylogeny and palaeobiology of Iberomeryx remain rather enigmatic. Only two species have been described: the type species I. parvus from the Benara locality in Georgia, and the Western European species I. minor reported from France, Spain, and Switzerland. Iberomeryx savagei from India has recently been placed in the new genus Nalameryx. All these localities are dated to the Rupelian and correspond mainly to MP23 (European mammal reference level). Based on the short height of the tooth-crown and the bunoselenodont pattern of the molars, Iberomeryx has often been considered as a folivore/frugivore. The I. minor remains from Soulce (NW Switzerland) are preserved in Rupelian lacustrine lithographic limestones. One specimen from this locality represents the most complete mandible of the taxon with a partially persevered ramus. Moreover, the unpreserved portion of the mandible left an imprint in the sediment, permitting the reconstruction of the mandible outline. Based on a new description of these specimens, anatomical comparisons and Relative Warp Analysis (24 landmarks) of 94 mandibles (11 fossil and 83 extant) from 31 ruminant genera (10 fossil and 21 extant) and 40 species (11 fossil and 29 extant), this study attempts a preliminary discussion of the phylogeny and the diet of the species I. minor. The results permit to differentiate Pecora and Tragulina on the first principal component axis (first Relative warp) on behalf of the length of the diastema c/cheek teeth, the length of the premolars and the angular process. The mandible shape of I. minor is similar to those of the primitive Tragulina, but it differs somewhat from those of the extant Tragulidae, the only extant family in the Tragulina. This difference is essentially due to a stockier mandible and a deeper incisura vasorum. However, in consideration of the general pattern of its cheek teeth, I. minor as well as possibly Nalameryx should be considered to represent the only known primitive Tragulidae from the Oligocene. Moreover, I. minor should have been a selective browser (fruit and dicot foliage) but, similarly to small Hypertragulidae and Tragulidae, may also have exceptionally consumed animal matter