Hidden structure in disordered proteins is adaptive to intracellular changes

Intrinsically disordered protein regions (IDRs) are ubiquitous in all proteomes and essential to cellular function. Unlike folded domains, IDRs exist in an ensemble of rapidly changing conformations. The sequence-encoded structural biases in IDR ensembles are important for function, but are difficult to resolve. Here, we reveal hidden structural preferences in IDR ensembles in vitro with two orthogonal structural methods (SAXS and FRET), and demonstrate that these structural preferences persist in cells using live cell microscopy. Importantly, we demonstrate that some IDRs have structural preferences that can adaptively respond to even mild intracellular environment changes, while other IDRs may display a remarkable structural resilience. We propose that the ability to sense and respond to changes in cellular physicochemical composition, or to resist such changes, is a sequence-dependent property of IDRs in organisms across all kingdoms of life.

Secondary Nucleation and the Conservation of Structural Characteristics of Amyloid Fibril Strains

Amyloid fibrils are ordered protein aggregates and a hallmark of many severe neurodegenerative diseases. Amyloid fibrils form through primary nucleation from monomeric protein, grow through monomer addition and proliferate through fragmentation or through the nucleation of new fibrils on the surface of existing fibrils (secondary nucleation). It is currently still unclear how amyloid fibrils initially form in the brain of affected individuals and how they are amplified. A given amyloid protein can sometimes form fibrils of different structure under different solution conditions in vitro, but often fibrils found in patients are highly homogeneous. These findings suggest that the processes that amplify amyloid fibrils in vivo can in some cases preserve the structural characteristics of the initial seed fibrils. It has been known for many years that fibril growth by monomer addition maintains the structure of the seed fibril, as the latter acts as a template that imposes its fold on the newly added monomer. However, for fibrils that are formed through secondary nucleation it was, until recently, not clear whether the structure of the seed fibril is preserved. Here we review the experimental evidence on this question that has emerged over the last years. The overall picture is that the fibril strain that forms through secondary nucleation is mostly defined by the solution conditions and intrinsic structural preferences, and not by the seed fibril strain.

Probing the Validity of the Zintl−Klemm Concept for Alkaline-Metal Copper Tellurides by Means of Quantum-Chemical Techniques

Understanding the nature of bonding in solid-state materials is of great interest for their designs, because the bonding nature influences the structural preferences and chemical as well as physical properties of solids. In the cases of tellurides, the distributions of valence-electrons are typically described by applying the Zintl−Klemm concept. Yet, do these Zintl−Klemm treatments provide adequate pictures that help us understanding the bonding nature in tellurides? To answer this question, we followed up with quantum-chemical examinations on the electronic structures and the bonding nature of three alkaline-metal copper tellurides, i.e., NaCu3Te2, K2Cu2Te5, and K2Cu5Te5. In doing so, we accordingly probed the validity of the Zintl−Klemm concept for these ternary tellurides, based on analyses of the respective projected crystal orbital Hamilton populations (−pCOHP) and Mulliken as well as Löwdin charges. Since all of the inspected tellurides are expected to comprise Cu−Cu interactions, we also paid particular attention to the possible presence of closed-shell interactions.

Innate Intracellular Antiviral Responses Restrict the Amplification of Defective Virus Genomes of Parainfluenza Virus 5

ABSTRACT During the replication of parainfluenza virus 5 (PIV5), copyback defective virus genomes (DVGs) are erroneously produced and are packaged into “infectious” virus particles. Copyback DVGs are the primary inducers of innate intracellular responses, including the interferon (IFN) response. While DVGs can interfere with the replication of nondefective (ND) virus genomes and activate the IFN-induction cascade before ND PIV5 can block the production of IFN, we demonstrate that the converse is also true, i.e., high levels of ND virus can block the ability of DVGs to activate the IFN-induction cascade. By following the replication and amplification of DVGs in A549 cells that are deficient in a variety of innate intracellular antiviral responses, we show that DVGs induce an uncharacterized IFN-independent innate response(s) that limits their replication. High-throughput sequencing was used to characterize the molecular structure of copyback DVGs. While there appears to be no sequence-specific break or rejoining points for the generation of copyback DVGs, our findings suggest there are region, size, and/or structural preferences selected for during for their amplification. IMPORTANCE Copyback defective virus genomes (DVGs) are powerful inducers of innate immune responses both in vitro and in vivo. They impact the outcome of natural infections, may help drive virus‐host coevolution, and promote virus persistence. Due to their potent interfering and immunostimulatory properties, DVGs may also be used therapeutically as antivirals and vaccine adjuvants. However, little is known of the host cell restrictions which limit their amplification. We show here that the generation of copyback DVGs readily occurs during parainfluenza virus 5 (PIV5) replication, but that their subsequent amplification is restricted by the induction of innate intracellular responses. Molecular characterization of PIV5 copyback DVGs suggests that while there are no genome sequence-specific breaks or rejoin points for the generation of copyback DVGs, genome region, size, and structural preferences are selected for during their evolution and amplification.

Revisiting the Zintl‒Klemm Concept for ALn2Ag3Te5-Type Alkaline-Metal (A) Lanthanide (Ln) Silver Tellurides

Understanding the bonding nature of solids is decisive, as knowledge of the bonding situation for any given material provides valuable information about its structural preferences and physical properties. Although solid-state tellurides are at the forefront of several fields of research, the electronic structures, particularly their nature of bonding, are typically understood by applying the Zintl‒Klemm concept. However, certain tellurides comprise ionic as well as strong (polar) mixed-metal bonds, in obvious contrast to the full valence-electron transfers expected by Zintl‒Klemm’s reasoning. How are the valence-electrons really distributed in tellurides containing ionic as well as mixed-metal bonds? To answer this question, we carried out bonding and Mulliken as well as Löwdin population analyses for the series of ALn2Ag3Te5-type tellurides (A = alkaline-metal; Ln = lanthanide). In addition to the bonding analyses, we provide a brief description of the crystal structure of this particular type of telluride, using the examples of RbLn2Ag3Te5 (Ln = Ho, Er) and CsLn2Ag3Te5 (Ln = La, Ce), which have been determined for the first time.