Current Protein and Peptide Science - Volume 21, Issue 1, 2020

Proteins can undergo kinetic/thermodynamic partitioning between folding and aggregation. Proper protein folding and thermodynamic stability are crucial for aggregation inhibition. Thus, proteinfolding principles have been widely believed to consistently underlie aggregation as a consequence of conformational change. However, this prevailing view appears to be challenged by the ubiquitous phenomena that the intrinsic and extrinsic factors including cellular macromolecules can prevent aggregation, independently of (even with sacrificing) protein folding rate and stability. This conundrum can be definitely resolved by ‘a simple principle’ based on a rigorous distinction between protein folding and aggregation: aggregation can be controlled by affecting the intermolecular interactions for aggregation, independently of the intramolecular interactions for protein folding. Aggregation is beyond protein folding. A unifying model that can conceptually reconcile and underlie the seemingly contradictory observations is described here. This simple principle highlights, in particular, the importance of intermolecular repulsive forces against aggregation, the magnitude of which can be correlated with the size and surface properties of molecules. The intermolecular repulsive forces generated by the common intrinsic properties of cellular macromolecules including chaperones, such as their large excluded volume and surface charges, can play a key role in preventing the aggregation of their physically connected polypeptides, thus underlying the generic intrinsic chaperone activity of soluble cellular macromolecules. Such intermolecular repulsive forces of bulky cellular macromolecules, distinct from protein conformational change and attractive interactions, could be the puzzle pieces for properly understanding the combined cellular protein folding and aggregation including how proteins can overcome their metastability to amyloid fibrils in vivo.

Insulin internalization and processing of the Insulin Receptor Complex (IRC) inside the cell are important components of the intracellular Mechanism of Insulin Action (MIA). They define the continuation of intracellular signaling of IRC and allow utilization of the parts of the complex after ligand dissociation. Traditionally, changes in the insulin regulatory system associated with the vertebrate phylogenesis have been evaluated by changes of its two elements: the hormone and its receptor. A hormone-competent cell was considered as an evolutionarily completed element of insulin regulatory system. However, previous studies of the isolated hepatocytes of four classes of vertebrates (lamprey, frog, chicken, and rat) revealed significant differences in the state of internalization of 125I-insulin and intracellular IRC processing. Radical differences were noted in the regulation of 125I-insulin internalization and the intracellular fate of the IRC. Here, cytosolic efficient insulin degradation and a complete lack of 125I-insulin exocytosis were observed in the cyclostome cells, whereas in amphibians the hormone underwent lysosomal degradation and showed low levels of exocytosis, while birds and mammals were characterized by high volumes of the excreted 125Iinsulin containing proteolytic 125I-insulin fragments. Despite the established recognition of the importance of the temperature factor, a complete understanding of the molecular mechanisms underlying the temperature effects on MIA is still missing. This poorly studied problem of the MIA temperature dependence can be behind the differences in the effect of temperature on the intracellular action of insulin and IGF-I. In fact, at different phylogenetic stages, successive changes were reported for the temperature dependence of the 125Iinsulin internalization and exocytosis. The following regularities were reported for the effect of temperature on the 125I-insulin internalization in isolated hepatocytes of different origin: complete lack of receptibility of the process to temperature in lampreys, receptibility of the process in a narrow range of low temperatures (0-5°C) in amphibians, and flexible regulation of 125I-insulin internalization in a wide temperature range (6- 37°C) in the cells from endothermic organisms. Reported data make it possible to observe three stages in the alteration of temperature regulation of 125I-insulin internalization (in cells of cyclostomes, amphibians, and endothermic organisms) and two stages of temperature regulation of 125I-insulin exocytosis in cells of amphibians, birds, and mammals. The data presented in this study reflect the specificity of the developmental reorganization of the intracellular MIA regulation and hormone utilization, and emphasize the central role of temperature in selective MIA formation during vertebrate phylogenesis.

Thaumatin-like proteins (TLPs) are a highly complex protein family associated with host defense and developmental processes in plants, animals, and fungi. They are highly diverse in angiosperms, for which they are classified as the PR-5 (Pathogenesis-Related-5) protein family. In plants, TLPs have a variety of properties associated with their structural diversity. They are mostly associated with responses to biotic stresses, in addition to some predicted activities under drought and osmotic stresses. The present review covers aspects related to the structure, evolution, gene expression, and biotechnological potential of TLPs. The efficiency of the discovery of new TLPs is below its potential, considering the availability of omics data. Furthermore, we present an exemplary bioinformatics annotation procedure that was applied to cowpea (Vigna unguiculata) transcriptome, including libraries of two tissues (root and leaf), and two stress types (biotic/abiotic) generated using different sequencing approaches. Even without using genomic sequences, the pipeline uncovered 56 TLP candidates in both tissues and stresses. Interestingly, abiotic stress (root dehydration) was associated with a high number of modulated TLP isoforms. The nomenclature used so far for TLPs was also evaluated, considering TLP structure and possible functions identified to date. It is clear that plant TLPs are promising candidates for breeding purposes and for plant transformation aiming a better performance under biotic and abiotic stresses. The development of new therapeutic drugs against human fungal pathogens also deserves attention. Despite that, applications derived from TLP molecules are still below their potential, as it is evident in our review.

Hormones are known to influence various body systems that include skeletal, cardiac, digestive, excretory, and immune systems. Emerging investigations suggest the key role played by secretions of endocrine glands in immune cell differentiation, proliferation, activation, and memory attributes of the immune system. The link between steroid hormones such as glucocorticoids and inflammation is widely known. However, the role of peptide hormones and amino acid derivatives such as growth and thyroid hormones, prolactin, dopamine, and thymopoietin in regulating the functioning of the immune system remains unclear. Here, we reviewed the findings pertinent to the functional role of hormone-immune interactions in health and disease and proposed perspective directions for translational research in the field.

Alzheimer's disease (AD) is the most common neurodegenerative disorder. The pathogenesis of AD is very complicated. For decades, the amyloid hypothesis has influenced and guided research in the field of AD. Meanwhile, researchers gradually realized that AD is caused by multiple concomitant factors, such as autophagy, mitochondrial quality control, insulin resistance and oxidative stress. In current clinical trials, the improvement strategies of AD, such as Aβ antibody immunotherapy and gamma secretase inhibitors, are limited. There is mounting evidence of neurodegenerative disorders indicated that activation of AMP-activated protein kinase (AMPK) may have broad neuroprotective effects. We reviewed the researches on AMPK for AD, the results demonstrated that activation of AMPK is controversial in Aβ deposition and tau phosphorylation, but is positive to promote autophagy, maintain mitochondrial quality control, reduce insulin resistance and relieve oxidative stress. It is concluded that AMPK might be a new target for AD by aggressively treating the risk factors in the future.

The oxidation of a vast range of phenolic and non-phenolic substrates has been catalyzed by laccases. Given a wide range of substrates, laccases can be applied in different biotechnological applications. The present review was conducted to provide a broad context in pharmaceutical- and biomedical- related applications of laccases for academic and industrial researchers. First, an overview of biological roles of laccases was presented. Furthermore, laccase-mediated strategies for imparting antimicrobial and antioxidant properties to different surfaces were discussed. In this review, laccase-mediated mechanisms for endowing antimicrobial properties were divided into laccase-mediated bio-grafting of phenolic compounds on lignocellulosic fiber, chitosan and catheters, and laccase-catalyzed iodination. Accordingly, a special emphasis was placed on laccase-mediated functionalization for creating antimicrobials, particularly chitosan-based wound dressings. Additionally, oxidative bio-grafting and oxidative polymerization were described as the two main laccase-catalyzed reactions for imparting antioxidant properties. Recent laccase-related studies were also summarized regarding the synthesis of antibacterial and antiproliferative agents and the degradation of pharmaceuticals and personal care products.

Butyrylcholinesterase is a serine hydrolase that catalyzes the hydrolysis of esters in the body. Unlike its sister enzyme acetylcholinesterase, butyrylcholinesterase has a broad substrate scope and lower acetylcholine catalytic efficiency. The difference in tissue distribution and inhibitor sensitivity also points to its involvement external to cholinergic neurotransmission. Initial studies on butyrylcholinesterase showed that the inhibition of the enzyme led to the increment of brain acetylcholine levels. Further gene knockout studies suggested its involvement in the regulation of amyloid-beta, a brain pathogenic protein. Thus, it is an interesting target for neurological disorders such as Alzheimer’s disease. The substrate scope of butyrylcholinesterase was recently found to include cocaine, as well as ghrelin, the “hunger hormone”. These findings led to the development of recombinant butyrylcholinesterase mutants and viral gene therapy to combat cocaine addiction, along with in-depth studies on the significance of butyrylcholinesterase in obesity. It is observed that the pharmacological impact of butyrylcholinesterase increased in tandem with each reported finding. Not only is the enzyme now considered an important pharmacological target, it is also becoming an important tool to study the biological pathways in various diseases. Here, we review and summarize the biochemical properties of butyrylcholinesterase and its roles, as a cholinergic neurotransmitter, in various diseases, particularly neurodegenerative disorders.