The impact of dust evolution on the dead zone outer edge in magnetized protoplanetary disks

[Abridged] Aims. We provide an important step toward a better understanding of the magnetorotational instability (MRI)-dust coevolution in protoplanetary disks by presenting a proof of concept that dust evolution ultimately plays a crucial role in the MRI activity. Methods. First, we study how a fixed power-law dust size distribution with varying parameters impacts the MRI activity, especially the steady-state MRI-driven accretion, by employing and improving our previous 1+1D MRI-driven turbulence model. Second, we relax the steady-state accretion assumption in this disk accretion model, and partially couple it to a dust evolution model in order to investigate how the evolution of dust (dynamics and grain growth processes combined) and MRI-driven accretion are intertwined on million-year timescales. Results. Dust coagulation and settling lead to a higher gas ionization degree in the protoplanetary disk, resulting in stronger MRI-driven turbulence as well as a more compact dead zone. On the other hand, fragmentation has an opposite effect because it replenishes the disk in small dust particles. Since the dust content of the disk decreases over million years of evolution due to radial drift, the MRI-driven turbulence overall becomes stronger and the dead zone more compact until the disk dust-gas mixture eventually behaves as a grain-free plasma. Furthermore, our results show that dust evolution alone does not lead to a complete reactivation of the dead zone. Conclusions. The MRI activity evolution (hence the temporal evolution of the MRI-induced $\alpha$-parameter) is controlled by dust evolution and occurs on a timescale of local dust growth, as long as there is enough dust particles in the disk to dominate the recombination process for the ionization chemistry. Once it is no longer the case, it is expected to be controlled by gas evolution and occurs on a viscous evolution timescale.Comment: 23 pages, 13 figures, Accepted for publication in A&

Molecular Principles of Gene Fusion Mediated Rewiring of Protein Interaction Networks in Cancer

Gene fusions are common cancer-causing mutations, but the molecular principles by which fusion protein products affect interaction networks and cause disease are not well understood. Here, we perform an integrative analysis of the structural, interactomic, and regulatory properties of thousands of putative fusion proteins. We demonstrate that genes that form fusions (i.e., parent genes) tend to be highly connected hub genes, whose protein products are enriched in structured and disordered interaction-mediating features. Fusion often results in the loss of these parental features and the depletion of regulatory sites such as post-translational modifications. Fusion products disproportionately connect proteins that did not previously interact in the protein interaction network. In this manner, fusion products can escape cellular regulation and constitutively rewire protein interaction networks. We suggest that the deregulation of central, interaction-prone proteins may represent a widespread mechanism by which fusion proteins alter the topology of cellular signaling pathways and promote cancer

Molecular determinants underlying functional innovations of TBP and their impact on transcription initiation.

Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265TATA-box binding protein (TBP) is required for every single transcription event in archaea and eukaryotes. It binds DNA and harbors two repeats with an internal structural symmetry that show sequence asymmetry. At various times in evolution, TBP has acquired multiple interaction partners and different organisms have evolved TBP paralogs with additional protein regions. Together, these observations raise questions of what molecular determinants (i.e. key residues) led to the ability of TBP to acquire new interactions, resulting in an increasingly complex transcriptional system in eukaryotes. We present a comprehensive study of the evolutionary history of TBP and its interaction partners across all domains of life, including viruses. Our analysis reveals the molecular determinants and suggests a unified and multi-stage evolutionary model for the functional innovations of TBP. These findings highlight how concerted chemical changes on a conserved structural scaffold allow for the emergence of complexity in a fundamental biological process

General approach to reversing ketol-acid reductoisomerase cofactor dependence from NADPH to NADH

To date, efforts to switch the cofactor specificity of oxidoreductases from nicotinamide adenine dinucleotide phosphate (NADPH) to nicotinamide adenine dinucleotide (NADH) have been made on a case-by- case basis with varying degrees of success. Here we present a straightforward recipe for altering the cofactor specificity of a class of NADPH-dependent oxidoreductases, the ketol-acid reductoisomerases (KARIs). Combining previous results for an engineered NADH-dependent variant of Escherichia coli KARI with available KARI crystal structures and a comprehensive KARI-sequence alignment, we identified key cofactor specificity determinants and used this information to construct five KARIs with reversed cofactor preference. Additional directed evolution generated two enzymes having NADH-dependent catalytic efficiencies that are greater than the wild-type enzymes with NADPH. High-resolution structures of a wild-type/variant pair reveal the molecular basis of the cofactor switch

Crystal structure of rhodopsin in complex with a mini-G_o sheds light on the principles of G protein selectivity

Selective coupling of G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs) to specific Gα-protein subtypes is critical to transform extracellular signals, carried by natural ligands and clinical drugs, into cellular responses. At the center of this transduction event lies the formation of a signaling complex between the receptor and G protein. We report the crystal structure of light-sensitive GPCR rhodopsin bound to an engineered mini-Go protein. The conformation of the receptor is identical to all previous structures of active rhodopsin, including the complex with arrestin. Thus, rhodopsin seems to adopt predominantly one thermodynamically stable active conformation, effectively acting like a “structural switch,” allowing for maximum efficiency in the visual system. Furthermore, our analysis of the well-defined GPCR–G protein interface suggests that the precise position of the carboxyl-terminal “hook-like” element of the G protein (its four last residues) relative to the TM7/helix 8 (H8) joint of the receptor is a significant determinant in selective G protein activation

Cotranslational protein assembly imposes evolutionary constraints on homomeric proteins

Cotranslational protein folding can facilitate rapid formation of functional structures. However, it might also cause premature assembly of protein complexes, if two interacting nascent chains are in close proximity. By analyzing known protein structures, we show that homomeric protein contacts are enriched towards the C-termini of polypeptide chains across diverse proteomes. We hypothesize that this is the result of evolutionary constraints for folding to occur prior to assembly. Using high-throughput imaging of protein homomers in vivo in E. coli and engineered protein constructs with N- and C-terminal oligomerization domains, we show that, indeed, proteins with C-terminal homomeric interface residues consistently assemble more efficiently than those with N-terminal interface residues. Using in vivo, in vitro and in silico experiments, we identify features that govern successful assembly of homomers, which have implications for protein design and expression optimization

Exploiting sequence and stability information for directing nanobody stability engineering

[Background] Variable domains of camelid heavy-chain antibodies, commonly named nanobodies, have highbiotechnological potential. In view of their broad range of applications in research, diagnostics and therapy,engineering their stability is of particular interest. One important aspect is the improvement of thermostability,because it can have immediate effects on conformational stability, protease resistance and aggregation pro-pensity of the protein[Methods] We analyzed the sequences and thermostabilities of 78 purified nanobody binders. From this data,potentially stabilizing amino acid variations were identified and studied experimentally.Results:Some mutations improved the stability of nanobodies by up to 6.1 °C, with an average of 2.3 °C acrosseight modified nanobodies. The stabilizing mechanism involves an improvement of both conformational stabilityand aggregation behavior, explaining the variable degree of stabilization in individual molecules. In some in-stances, variations predicted to be stabilizing actually led to thermal destabilization of the proteins. The reasonsfor this contradiction between prediction and experiment were investigated.[Conclusions] The results reveal a mutational strategy to improve the biophysical behavior of nanobody bindersand indicate a species-specificity of nanobody architecture[General significance] This study illustrates the potential and limitations of engineering nanobody thermostabilityby merging sequence information with stability data, an aspect that is becoming increasingly important with therecent development of high-throughput biophysical methodsWe thank NanoTemper Technologies in Munich for its generous support with free DSF measurements. Funding by the European Union(grantnumber: Health-F4-2010-241481) as part of the Affinomics consortium is gratefully acknowledged.Peer reviewe