Current Protein and Peptide Science - Volume 15, Issue 8, 2014

Cytochrome b561 (CYB561) proteins are ascorbate reducible, trans-membrane proteins consisting of 200-300 amino acids, about half of which are hydrophobic. The first identified CYB561 protein was discovered more than 40 years ago, and is localized in the chromaffin granule membrane of the mammalian adrenal glands. Proteins with similar structural elements and biophysical and biochemical properties were identified in a wide range of animal and plant phyla in the past 15 years. CYB561 proteins have six trans-membrane helices and two b-type hemes, one on each side of the membrane. The two heme-b centers are coordinated by two pairs of His residues localized in the central four trans-membrane domains, probably very close to the membrane interface. The midpoint redox potentials of the two hemes are above 0 mV and about 100 mV apart from each other. These proteins are different in many respects from the well-known two heme-bcontaining, trans-membrane b-type cytochromes localized in the inner membrane of mitochondria, in the chloroplast thylakoids or in the cell membrane. The atomic-level structure of only one CYB561 protein is available to date. In this paper we discuss in detail the biophysical and biochemical properties of the CYB561 proteins and provide a short overview of their known or putative biological functions and significance.

Specific receptors for classical neurotransmitters and neuropeptides, as well as the Na+, K+-ATPase, are all molecular entities inserted into synaptic region membranes and localized contiguously. Herein, available experimental evidence showing close interactions between the activity of the Na+, K+-ATPase and the N-methyl-D-aspartate (NMDA) ionotropic glutamate receptor was reviewed, supporting a functional link between these macromolecules. The Na+, K+- ATPase and NMDA receptor are involved in ion movements through membranes. The former acts as an ion transporter, whereas the latter acts as an ion channel. The modulation of their activity plays a critical role in controlling neuronal function. Examples were taken from studies performed with specific agonists or antagonists of the NMDA receptor. Regarding the Na+, K+-ATPase, its involvement was postulated after observing its inhibition by ouabain or related cardiac glycosides. Additionally, experimental conditions known to prevent normal Na+, K+-ATPase (i. e., sodium pump functioning) led to similar valuable information. These findings indicate potential cross-talk between this enzyme and the NMDA receptor. The Na+, K+-ATPase and NMDA play very important roles in the regulation of learning and memory in the hippocampus. The fact that important changes here described were recorded in the hippocampus indicate a different vulnerability of this area to toxicity induced by the Na+, K+-ATPase inhibitor ouabain. Some interesting relationships include calcineurin actions, the participation of ERK or Src family kinases, and signaling cascades initiated by calcium. At present, many other examples of signaling related to the NMDA receptor cannot be correlated with Na+, K+-ATPase activity. It is desirable that the development of future research offer new clues for the relationship between Na+, K+-ATPase and NMDA receptor activation.

Lactoferrin or lactotransferrin is a multifunctional glycoprotein found in blood circulation, mucosal surfaces, neutrophils, and in various secretory fluids, such as milk, bile, tears, nasal secretion, pancreatic juice, and saliva. The lactoferrin content in milk varies between different mammalian species and, within one species, between lactation periods. Although lactoferrin is known to be involved with immunoprotection, its functions are not limited to the regulation of innate immunity, but extend to iron transfer to cells, control of the level of free iron in blood and external secretions, interaction with DNA, RNA, heparin, and polysaccharides, and pronounced antimicrobial and antiviral activities. This multifunctionality is determined by the fact that lactoferrin belongs to the class of hybrid proteins possessing both ordered domains and functionally important intrinsically disordered regions. Structurally, lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa consisting of two homologous domains known as N-terminal and C-terminal lobes. These lobes are unevenly glycosylated (with the C-lobe typically containing more N-linked glycosylation sites). Each lobe can bind a single ferric ion concomitantly with one bicarbonate anion. Lactoferrin and its lobes have a wide spectrum of antimicrobial and antiviral activities, with the antimicrobial and antiviral potentials dependent on the type of microbes and viruses. Often, the N-lobe possesses the majority of antimicrobial activities. In addition, lactoferrin and its lobes possess clear anti-cancer, wound healing, anti-inflammatory, and immunomodulation activities.

The Sigma Receptor 1 (sig-1R) is a protein present in numerous normal tissues, such as brain, retina, lens, liver, lung, heart, but also in many tumor lines. Its amino acid sequence is homologous to fungal C-8,7 sterol isomerase, but it has no known homology with mammalian proteins and does not possess sterol isomerase activity. It is localized in plasma and ER membranes, and its exact function is not clarified as of yet. Last reports point to its participation in regulation of ionic channels activity, particularly calcium channels. Application of numerous synthetic ligands of sigma1 receptor provided means to study its protective effects and metabolic functions in different tissues. This review describes influence of sigma1 receptor on various aspects of cellular metabolism, such as calcium signalling, mitochondrial functions, oxidative stress, survival and apoptotic pathways, and tumor cells proliferation.

Endoplasmic reticulum (ER) stress is characterized by the accumulation of unfolded and misfolded proteins in the ER lumen. Unfolded and misfolded protein accumulation interferes with the ER function and triggers ER stress response. Thus, ER stress response, also called unfolded protein response (UPR), is an adaptive process that controls the protein amount in the ER lumen and the downstream protein demand. In normal conditions, the role of ER stress is to maintain ER homeostasis, restore ER function, and protect stressed cells from apoptosis, by coordinating gene expression, protein synthesis, and accelerating protein degradation through several molecular pathways. However, prolonged ER stress response plays a paradoxical role, which leads to cell damage, apoptosis, and concomitant tissue injuries. A number of tissue alterations are involved with diabetes mellitus progress and its comorbidities via ER stress. However, certain pharmacological agents affecting ER stress have been identified. In this review, we summarized the relationship between ER stress and insulin resistance development. Moreover, we aim to explain how ER stress influences type 2 diabetes mellitus (T2DM) development. In addition, we reviewed the literature on ER stress and UPR in three kinds of tissue injuries induced by T2DM. Finally, a retrospective analysis of the effects of anti-diabetes medications on ER stress is presented.

The prevailing view is that not only can some of the tumor antigens be used as biosensors for cancers, but also they may indeed be used as targets for immunotherapy. The identification of tumor antigens becomes a vital step in oncology research. Both the humoral immune system and the cellular immune system are activated in response to a tumor antigen in vivo of patients with tumor. Immune effector molecules and cells can be used to screen and identify tumor antigens. Specific T cells, including CD8+ and CD4+ T cells, can identify T cell epitopes, and specific antibodies in sera can identify B cell epitopes. The researchers have studied this area for decades. Initially, they explored tumor antigens with the use of 1-D SDS–PAGE and sandwich ELISAs. Since 1990s, CTL screening approach and peptide elution approach had been established. After that, SEREX, SERPA and protein microarray technology have become the mainstream highthroughput strategies for identifying tumor antigens. There are some other approaches, such as combinatorial peptide libraries, representational difference analysis of cDNA and bioinformatics methods. This review’s aim is to describe the generation, the theory, the key protocols and the application of some main techniques and provide their benefits and drawbacks.

The antiaging protein of Klotho is a transmembrane protein mainly expressed in the kidney, parathyroid glands and choroid plexus of the brain. The Klotho protein exists in two forms, a full-length membrane form and a soluble secreted form. The extracellular domain of Klotho can be enzymatically cleaved off and released into the systemic circulation where it acts as β-glucuronidase and a hormone. Soluble Klotho can be found in the blood, cerebrospinal fluid, and the urine of mammals. Klotho deficiency results in early appearance of multiple age-related disorders and premature death, whereas overexpression of Klotho exerts the opposite effect. Klotho may influence cellular transport processes across the cell membrane by inhibiting calcitriol (1,25(OH) (2)D(3)), formation or by directly affecting transporter proteins, including ion channels, carriers and pumps. Accordingly, Klotho protein is a powerful regulator of transport mechanisms across the cell membrane. Klotho regulates diverse calcium and potassium ion channels, as well as several carriers including the Na+-coupled excitatory amino acid transporters EAAT3 and EAAT4, the Na+-coupled phosphate cotransporters, NaPi-IIa and NaPi-IIb, and a Na+/K+-ATPase. All those cellular transport regulations contribute in the aging suppressor role of Klotho. Future studies will help to determine if the Klotho protein regulates cell-surface expression of other transport proteins and is affecting underlying mechanisms.

Psoriasin (S100A7) is one of the members in the S100 protein family. It was first discovered as a protein abundantly expressed in psoriatic keratinocytes. Psoriasin has been implicated in a wide range of intracellular and extracellular functions, including regulation of calcium homeostasis, cell proliferation, differentiation, apoptosis, cell invasion and motility, cytoskeleton dynamics, protein phosphorylation, regulation of transcriptional factors, immune responses, chemotaxis, inflammation and pluripotency. Altered expression of psoriasin was shown to associate with a broad range of diseases, including inflammatory and immune disorders and tumors. Many lines of evidence suggested that psoriasin exerts its distinct functions through alterations in both intracellular and extracellular pathways and results alteration in gene expression. In this review, we summarize the multiple function of psoriasin and the underlying mechanisms and discuss the potential role of psoriasin as one of the biomarkers and therapeutic targets for multiple diseases.