Multi-Site Red-Edge Excitation Shift Reveals the Residue-Specific Solvation Dynamics during the Native to Amyloid-like Transition of an Amyloidogenic Protein.

Changes in water-protein interactions are crucial for proteins to achieve functional and nonfunctional conformations during structural transitions by modulating local stability. Amyloid-like protein aggregates in deteriorating neurons are hallmarks of neurodegenerative disorders. These aggregates form through significant structural changes, transitioning from functional native conformations to supramolecular cross-β-sheet structures via misfolded and oligomeric intermediates in a multistep process.

Deciphering the Monomeric and Dimeric Conformational Landscapes of the Full-Length TDP-43 and the Impact of the C-Terminal Domain.

The aberrant aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in cells leads to the pathogenesis of multiple fatal neurodegenerative diseases. Decoding the proposed initial transition between its functional dimeric and aggregation-prone monomeric states can potentially design a viable therapeutic strategy, which is presently limited by the lack of structural detail of the full-length TDP-43. To achieve a complete understanding of such a delicate phase space, we employed a multiscale simulation approach that unearths numerous crucial features, broadly summarized in two categories: (1) state-independent features that involve inherent chain collapsibility, rugged polymorphic landscape dictated by the terminal domains, high β-sheet propensity, structural integrity preserved by backbone-based intrachain hydrogen bonds and electrostatic forces, the prominence of the C-terminal domain in the intrachain cross-domain interfaces, and equal participation of hydrophobic and hydrophilic (charged and polar) residues in cross-domain interfaces; and (2) dimerization-modulated characteristics that encompass slower collapsing dynamics, restricted polymorphic landscape, the dominance of side chains in interchain hydrogen bonds, the appearance of the N-terminal domain in the dimer interface, and the prominence of hydrophilic (specifically polar) residues in interchain homo- and cross-domain interfaces.

Identification of a Hidden, Highly Aggregation-Prone Intermediate of Full-Length TDP-43 That Triggers its Misfolding and Amyloid Aggregation.

In cells, TDP-43 is a crucial protein that can form harmful amyloid aggregates linked to fatal and incurable human neurodegenerative disorders. Normally, TDP-43 exists in a smaller soluble native state that prevents aggregation. However, aging and stress can destabilize this native state, leading to the formation of disease-causing amyloid aggregates via the formation of partially unfolded, high-energy intermediates with a greater tendency to aggregate.

DNA-Mediated Formation of Phase-Separated Coacervates of the Nucleic Acid-Binding Domain of TAR DNA-Binding Protein (TDP-43) Prevents Its Amyloid-Like Misfolding.

Sequestration of protein molecules and nucleic acids to stress granules is one of the most promising strategies that cells employ to protect themselves from stress. In vitro, studies suggest that the nucleic acid-binding domain of TDP-43 (TDP-43) undergoes amyloid-like aggregation to β-sheet-rich structures in low pH stress. In contrast, we observed that the TDP-43 undergoes complex coacervation in the presence of ssDNA to a dense and light phase, preventing its amyloid-like aggregation.

Conformational Enigma of TDP-43 Misfolding in Neurodegenerative Disorders.

Misfolding and aggregation of the protein remain some of the most common phenomena observed in neurodegeneration. While there exist multiple neurodegenerative disorders characterized by accumulation of distinct proteins, what remains particularly interesting is the ability of these proteins to undergo a conformational change to form aggregates. TDP-43 is one such nucleic acid binding protein whose misfolding is associated with many neurogenerative diseases including amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD).

Electrostatics Choreographs the Aggregation Dynamics of Full-Length TDP-43 via a Monomeric Amyloid Precursor.

TDP-43 is a ubiquitously expressed, multidomain functional protein that is distinctively known to form aggregates in many fatal neurodegenerative disorders. However, the information for arresting TDP-43 aggregation is missing due to a lack of understanding of the molecular mechanism of the aggregation and structural properties of TDP-43. TDP-43 is inherently prone to aggregation and has minimal protein solubility.

Electrostatic Modulation of Intramolecular and Intermolecular Interactions during the Formation of an Amyloid-like Assembly.

The mechanism of protein aggregation can be broadly viewed as a shift from the native-state stabilizing intramolecular to the aggregated-phase sustaining intermolecular interactions. Understanding the role of electrostatic forces on the extent of modulation of this switch has recently evolved as a topic of monumental significance as protein aggregation has lately been connected to charge modifications of an aging proteome. To decipher the distinctive role of electrostatic forces on the extremely complicated phase separation landscape, we opted for a combined in vitro-in silico approach to ascertain the structure-dynamics-stability-aggregability relationship of the functional tandem RRM domains of the ALS-related protein TDP-43 (TDP-43), under a bivariate solution condition in terms of pH and salt concentration.

Thermodynamic modulation of folding and aggregation energy landscape by DNA binding of functional domains of TDP-43.

TDP-43 is a vital nucleic acid binding protein which forms stress-induced aberrant aggregates in around 97% cases of ALS, a fatal neurodegenerative disease. The functional tandem RRM domain of the protein (TDP-43) has been shown to undergo amyloid-like aggregation under stress in a pH-dependent fashion. However, the underlying thermodynamic and molecular basis of aggregation and how the energy landscape of folding, stability, and aggregation are coupled and modulated by nucleic acid binding is poorly understood.

Shapeshifter TDP-43: Molecular mechanism of structural polymorphism, aggregation, phase separation and their modulators.

TDP-43 is a nucleic acid-binding protein that performs physiologically essential functions and is known to undergo phase separation and aggregation during stress. Initial observations have shown that TDP-43 forms heterogeneous assemblies, including monomer, dimer, oligomers, aggregates, phase-separated assemblies, etc. However, the significance of each assembly of TDP-43 concerning its function, phase separation, and aggregation is poorly known.

Multistep molecular mechanism of amyloid-like aggregation of nucleic acid-binding domain of TDP-43.

TDP-43 protein is associated with many neurodegenerative diseases and has been shown to adopt various oligomeric and fibrillar states. However, a detailed kinetic understanding of the structural transformation of the native form of the protein to the fibrillar state is missing. In this study, we delineate the temporal sequence of structural events during the amyloid-like assembly of the functional nucleic acid-binding domain of TDP-43.

Dry Molten Globule-Like Intermediates in Protein Folding, Function, and Disease.

The performance of a protein depends on its correct folding to the final functional native form. Hence, understanding the process of protein folding has remained an important field of research for the scientific community for the past five decades. Two important intermediate states, namely, wet molten globule (WMG) and dry molten globule (DMG), have emerged as critical milestones during protein folding-unfolding reactions.

Effect of Solvation Conditions on Inter- and Intramolecular Assembly of Full-Length TDP-43.

Cellular stress is a major cause of neurodegenerative diseases. In particular, in amyotrophic lateral sclerosis (ALS), around 90% of the cases are believed to occur due to aggregation and misfolding of TDP-43 protein in neurons due to aging and chronic environmental stress. However, the physicochemical basis of how TDP-43 senses the change in solvation conditions during stress and misfolds remains very poorly understood.

The native state conformational heterogeneity in the energy landscape of protein folding.

The native structure of proteins is central to various functions performed by cells. A vital part of the structure-function paradigm of proteins is their inherent flexibility and dynamics. The dynamic interconversion between the conformational substates in the heterogeneous native state basin of the energy landscape enables a single protein molecule to perform multiple functions.

Assessment of antioxidant and cytotoxicity activities against A-549 lung cancer cell line by synthesized reduced graphene oxide nanoparticles mediated by .

Unlabelled: (green tea leaves) which acts as a reducing agent was used for the reduction of graphene oxide (GO) to obtain reduced graphene oxide (RGO). Anionic surfactant SDS was used to enhance the stability of synthesized reduced graphene oxide nanoparticles. Characterized reduced graphene oxide nanoparticle grain size was calculated to be 3.

Protonation-Deprotonation Switch Controls the Amyloid-like Misfolding of Nucleic-Acid-Binding Domains of TDP-43.

Nutrient starvation stress acidifies the cytosol and leads to the formation of large protein assemblies and misfolded aggregates. However, how starvation stress is sensed at the molecular level and leads to protein misfolding is poorly understood. TDP-43 is a vital protein, which, under stress-like conditions, associates with stress granule proteins via its functional nucleic-acid-binding domains (TDP-43) and misfolds to form aberrant aggregates.

Kinetic modeling and statistical optimization of submerged production of anti-Parkinson's prodrug -DOPA by .

-DOPA, a precursor of dopamine, is the drug of choice for Parkinson's disease, which persists due to decreased levels of dopamine in the brain. Present study emphasis the microbial production of -DOPA rather than the biotransformation of -DOPA by L-tyrosine. The production of -DOPA by bacterial isolates had gained more acceptance due to its more straightforward extraction and downstream processes.

A pH-dependent protein stability switch coupled to the perturbed pKa of a single ionizable residue.

The contribution of electrostatic interactions in protein stability has not been fully understood. Burial of an ionizable amino acid inside the hydrophobic protein core can affect its ionization equilibrium and shift its pKa differentially in the native (N) and unfolded (U) states of a protein and this coupling between the folding/unfolding cycle and the ionization equilibria of the ionizable residue can substantially influence the protein stability. Here, we studied the coupling of the folding/unfolding cycle with the ionization of a buried ionizable residue in a multi-domain protein, Human Serum Albumin (HSA) using fluorescence spectroscopy.

Preparation, characterization and application of curcumin based polymeric bio-composite for efficient removal of endotoxins and bacterial cells from therapeutic preparations.

Polymer science offers a great insight and a new research dimension for biomedical applications. The synthesis of polymeric materials by the physical ways provides several advantages over the conventional chemical methods. It is though expansive but less toxic, stable, and efficiently reproducible.

Indicator dye based screening of glutaminase free L-asparaginase producer and kinetic evaluation of enzyme production process.

Several soil isolates from 1 g of soil sample were isolated and screened for the production of L-asparaginase. Primary screening was performed using rapid plate assay; dye indicator studies were conducted, and phenol red with 0.005% concentration was found to be optimum.

Production and purification of bioflocculants from newly isolated bacterial species: a comparative decolourization study of cationic and anionic textile dyes.

Bioflocculant-producing bacteria were isolated from various water reservoirs and sediments of the water treatment plant. Four promising strains were identified by standard biochemical methods and 16s rRNA gene sequencing. Bioflocculants were produced in a batch bioreactor of 3 L under optimized conditions.

Early Metastable Assembly during the Stress-Induced Formation of Worm-like Amyloid Fibrils of Nucleic Acid Binding Domains of TDP-43.

TDP-43 protein travels between the cytosol and the nucleus to perform its nucleic acid binding functions through its two tandem RNA recognition motif domains (TDP-43). When exposed to various environmental stresses, it forms abnormal aggregates in the cytosol of neurons, which are the hallmarks of amyotrophic lateral sclerosis and other TDP-43 proteinopathies. However, the nature of early structural changes upon stress sensing and the consequent steps during the course of aggregation are not well understood.

Production, purification and kinetic characterization of glutaminase free anti-leukemic L-asparaginase with low endotoxin level from novel soil isolate.

Anti-leukemic enzyme L-asparaginase despite having significant applicability in medicine, holds side effects attributed to glutaminase activity and endotoxin content. Glutaminase activity proves to be toxic to non-tumor cells as glutamine is an essential amino acid. Endotoxin illicit the production of vasoactive amines and induce septic shock.

Correction: A dry molten globule-like intermediate during the base-induced unfolding of a multidomain protein.

Correction for 'A dry molten globule-like intermediate during the base-induced unfolding of a multidomain protein' by Nirbhik Acharya et al., Phys. Chem.

Coexistence of Gonadal Dysgenesis and Mullerian Agenesis in a Female with 46 XX Karyotype: A Case Report.

Gonadal dysgenesis is a rare genetically heterogeneous disorder characterized by underdeveloped ovaries with consequent, impuberism, primary amenorrhea, and hypergonadotropic hypogonadism. Mullerian agenesis or Mayer‑Rokitansky‑Kuster‑Hauser syndrome is characterized by congenital aplasia of the uterus and the upper part (2/3) of the vagina in a woman with normal development of secondary sexual characteristics and a normal 46 XX karyotype. The association of gonadal dysgenesis and Mayer-Rokitansky-Kuster-Hauser syndrome is very rare and appears to be coincidental.