Current Protein and Peptide Science - Volume 20, Issue 6, 2019

In the medical field, drug-target interactions are very important for the diagnosis and treatment of diseases, they also can help researchers predict the link between biomolecules in the biological field, such as drug-protein and protein-target correlations. Therefore, the drug-target research is a very popular study in both the biological and medical fields. However, due to the limitations of manual experiments in the laboratory, computational prediction methods for drug-target relationships are increasingly favored by researchers. In this review, we summarize several computational prediction models of the drug-target connections during the past two years, and briefly introduce their advantages and shortcomings. Finally, several further interesting research directions of drug-target interactions are listed.

The transcription factor Sox2 plays an important role in various phases of embryonic development, including cell fate and differentiation. These key regulatory functions are facilitated by binding to specific DNA sequences in combination with partner proteins to exert their effects. Recently, overexpression and gene amplification of Sox2 has been associated with tumor aggression and metastasis in various cancer types, including breast, prostate, lung, ovarian and colon cancer. All the different roles for Sox2 involve complicated regulatory networks consisting of protein-protein and protein-nucleic acid interactions. Their involvement in the EMT modulation is possibly enabled by Wnt/ β-catenin and other signaling pathways. There are number of in vivo models which show Sox2 association with increased cancer aggressiveness, resistance to chemo-radiation therapy and decreased survival rate suggesting Sox2 as a therapeutic target. This review will focus on the different roles for Sox2 in metastasis and tumorigenesis. We will also review the mechanism of action underlying the cooperative Sox2- DNA/partner factors binding where Sox2 can be potentially explored for a therapeutic opportunity to treat cancers.

α1-acid glycoprotein (orosomucoid, AGP) is an Acute Phase Protein produced by liver and peripheral tissues in response to systemic reaction to inflammation. AGP functions have been studied mostly in human, cattle and fish, although the protein has been also found in many mammalian species and birds. AGP fulfils at least two set of functions, which are apparently different from each other but in fact intimately linked. On one hand, AGP is an immunomodulatory protein. On the other hand, AGP is one of the most important binding proteins in plasma and, beside modulating pharmacokinetics and pharmacodynamics of many drugs, it is also able to bind and transport several endogen ligands related to inflammation. The focus of this review is the immunomodulatory activity of AGP. This protein regulates every single event related to inflammation, including binding of pathogens and modulating white blood cells activity throughout the entire leukocyte attacking sequence. The regulation of AGP activity is complex: the inflammation induces not only an increase in AGP serum concentration, but also a qualitative change in its carbohydrate moiety, generating a multitude of glycoforms, each of them with different, and sometimes opposite and contradictory, activities. We also present the most recent findings about the relationship between AGP and adipose tissue: AGP interacts with leptin receptor and, given its immunomodulatory function, it may be included among the potential players in the field of immunometabolism.

A major question in cell and cancer biology is concerned with understanding the flow of information from gene to protein. Indeed, many studies indicate that the proteome can be decoupled from the transcriptome. A major source of this decoupling is post-transcriptional regulation. The eukaryotic translation initiation factor eIF4E serves as an excellent example of a protein that can modulate the proteome at the post-transcriptional level. eIF4E is elevated in many cancers thus highlighting the relevance of this mode of control to biology. In this review, we provide a brief overview of various functions of eIF4E in RNA metabolism e.g. in nuclear-cytoplasmic RNA export, translation, RNA stability and/or sequestration. We focus on the modalities of eIF4E regulation at the biochemical and particularly structural level. In this instance, we describe not only the importance for the m7Gcap eIF4E interaction but also of recently discovered non-traditional RNA-eIF4E interactions as well as cap-independent activities of eIF4E. Further, we describe several distinct structural modalities used by the cell and some viruses to regulate or co-opt eIF4E, substantially extending the types of proteins that can regulate eIF4E from the traditional eIF4E-binding proteins (e.g. 4E-BP1 and eIF4G). Finally, we provide an overview of the results of targeting eIF4E activity in the clinic.

Several molecular mechanisms are involved in the regulation of skeletal muscle function. Among them, mitochondrial activity can be identified. The mitochondria is an important and essential organelle in the skeletal muscle that is involved in metabolic regulation and ATP production, which are two key elements of muscle contractibility and plasticity. Thus, in this review, we present the critical and recent antecedents regarding the mechanisms through which mitochondrial dysfunction can be involved in the generation and development of skeletal muscle pathologies, its contribution to detrimental functioning in skeletal muscle and its crosstalk with other typical signaling pathways related to muscle diseases. In addition, an update on the development of new strategies with therapeutic potential to inhibit the deleterious impact of mitochondrial dysfunction in skeletal muscle is discussed.

Substrate pleiotropicity, a very acidic phosphorylation consensus sequence, and an apparent uncontrolled activity, are the main features of CK2, a Ser/Thr protein kinase that is required for a plethora of cell functions. Not surprisingly, CK2 appears to affect cytoskeletal structures and correlated functions such as cell shape, mechanical integrity, cell movement and division. This review outlines our current knowledge of how CK2 regulates cytoskeletal structures, and discusses involved pathways and molecular mechanisms.

Amyloid aggregation is linked to an increasing number of human disorders from nonneurological pathologies such as type-2 diabetes to neurodegenerative ones such as Alzheimer or Parkinson’s diseases. Thirty-six human proteins have shown the capacity to aggregate into pathological amyloid structures. To date, it is widely accepted that amyloid folding/aggregation is a universal process present in eukaryotic and prokaryotic cells. In the last decade, several studies have unequivocally demonstrated that bacterial inclusion bodies – insoluble protein aggregates usually formed during heterologous protein overexpression in bacteria – are mainly composed of overexpressed proteins in amyloid conformation. This fact shows that amyloid-prone proteins display a similar aggregation propensity in humans and bacteria, opening the possibility to use bacteria as simple models to study amyloid aggregation process and the potential effect of both anti-amyloid drugs and pro-aggregative compounds. Under these considerations, several in vitro and in cellulo methods, which exploit the amyloid properties of bacterial inclusion bodies, have been proposed in the last few years. Since these new methods are fast, simple, inexpensive, highly reproducible, and tunable, they have aroused great interest as preliminary screening tools in the search for anti-amyloid (beta-blocker) drugs for conformational diseases. The aim of this mini-review is to compile recently developed methods aimed at tracking amyloid aggregation in bacteria, discussing their advantages and limitations, and the future potential applications of inclusion bodies in anti-amyloid drug discovery.

Alzheimer’s Disease (AD) is a form of progressive dementia involving cognitive impairment, loss of learning and memory. Different proteins (such as amyloid precursor protein (APP), β- amyloid (Aβ) and tau protein) play a key role in the initiation and progression of AD. We review the role of the most important proteins and peptides in AD pathogenesis. The structure, biosynthesis and physiological role of APP are shortly summarized. The details of trafficking and processing of APP to Aβ, the cytosolic intracellular Aβ domain (AICD) and small soluble proteins are shown, together with other amyloid-forming proteins such as tau and α-synuclein (α-syn). Hypothetic physiological functions of Aβ are summarized. The mechanism of conformational change, the formation and the role of neurotoxic amyloid oligomeric (oAβ) are shown. The fibril formation process and the co-existence of different steric structures (U-shaped and S-shaped) of Aβ monomers in mature fibrils are demonstrated. We summarize the known pathogenic and non-pathogenic mutations and show the toxic interactions of Aβ species after binding to cellular receptors. Tau phosphorylation, fibrillation, the molecular structure of tau filaments and their toxic effect on microtubules are shown. Development of Aβ and tau imaging in AD brain and CSF as well as blood biomarkers is shortly summarized. The most probable pathomechanisms of AD including the toxic effects of oAβ and tau; the three (biochemical, cellular and clinical) phases of AD are shown. Finally, the last section summarizes the present state of Aβ- and tau-directed therapies and future directions of AD research and drug development.

Lectins are defined as proteins or glycoproteins capable of specific and reversible binding to carbohydrates. Inside this group of proteins, the most well-studied lectins belong to the Leguminosae family, and inside this family, the Diocleinae subtribe includes the most characterized lectin Concanavalin A (ConA), as well as ConBr, the lectin from Canavalia brasiliensis, the subject of this review. Since 1979, several studies have been published in the literature regarding this lectin, from its isolation and characterization to its several biological activities. This year, 2019, will mark 40 years since researchers have begun to study ConBr and 100 years since the discovery of ConA, making 2019 a momentous year for lectinology. Owing to the abundance of studies involving ConBr, this review will focus on ConBr’s purification, physicochemical properties, functional and structural analyses, biological activities and biotechnological applications. This will give researchers a broad glimpse into the potential of this lectin, as well as it characteristics, as we look ahead to its expanding applications in glycomics and biotechnology.

The present review focuses on adipocytes-released peptides known to be involved in the control of gastrointestinal motility, acting both centrally and peripherally. Thus, four peptides have been taken into account: leptin, adiponectin, nesfatin-1, and apelin. The discussion of the related physiological or pathophysiological roles, based on the most recent findings, is intended to underlie the close interactions among adipose tissue, central nervous system, and gastrointestinal tract. The better understanding of this complex network, as gastrointestinal motor responses represent peripheral signals involved in the regulation of food intake through the gut-brain axis, may also furnish a cue for the development of either novel therapeutic approaches in the treatment of obesity and eating disorders or potential diagnostic tools.

Polymorphism is a specific feature of the amyloid structures. We have studied the amyloid structures and the process of their formation using the synthetic and recombinant preparations of Aβ peptides and their three fragments. The fibrils of different morphology were obtained for these peptides. We suppose that fibril formation by Aβ peptides and their fragments proceeds according to the simplified scheme: destabilized monomer → ring-like oligomer → mature fibril that consists of ringlike oligomers. We are the first who did 2D reconstruction of amyloid fibrils provided that just a ringlike oligomer is the main building block in fibril of any morphology, like a cell in an organism. Taking this into account it is easy to explain the polymorphism of fibrils as well as the splitting of mature fibrils under different external actions, the branching and inhomogeneity of fibril diameters. Identification of regions in the protein chains that form the backbone of amyloid fibril is a direction in the investigation of amyloid formation. It has been demonstrated for Aβ(1-42) peptide and its fragments that their complete structure is inaccessible for the action of proteases, which is an evidence of different ways of association of ring-like oligomers with the formation of fibrils. Based on the electron microscopy and mass spectrometry data, we have proposed a molecular model of the fibril formed by both Aβ peptide and its fragments. In connection with this, the unified way of formation of fibrils by oligomers, which we have discovered, could facilitate the development of relevant fields of medicine of common action.