Current Protein and Peptide Science - Volume 16, Issue 6, 2015

Integrase interactor 1 (INI1/hSNF5) is a core component of the SWI/SNF chromatin remodeling complex that alters the structure of chromatin in order to facilitate DNA-dependent cellular processes like transcription, replication, and repair. Integrase interactor 1 (INI1/hSNF5) is a core component of the SWI/SNF chromatin remodeling complex that alters the structure of chromatin in order to facilitate DNA-dependent cellular processes like transcription, replication, and repair. INI1/hSNF5 plays an important role in a variety of cellular processes. Inactivation of the Snf5 gene in mice leads to embryonic lethality suggesting a critical role for INI1/hSNF5 in cellular function, viability, and development. Biallelic loss-of-function of INI1/hSNF5 leads to certain cancers, most frequently rhabdoid tumors, demonstrating that INI1/hSNF5 is a tumor suppressor gene. INI1/hSNF5 regulates several essential steps in the propagation of the HIV-1 virus within the host cell, particularly HIV-1 integration. The mode of function of INI1/hSNF5 is only beginning to be understood. Given its importance in the normal functioning of the cell and its association with two diseases with high morbidity and mortality rates, it is imperative that the functions of this protein is delineated in greater detail in order to develop therapeutic interventions in certain cancers and AIDS. In this review, I have summarized the literature of published results on INI1/hSNF5 with emphasis on its molecular organization, role in different cellular pathways and involvement in AIDS and cancer.

Protein ADP-ribosylation is an important posttranslational modification that plays versatile roles in multiple biological processes. ADP-ribosylation is catalyzed by a group of enzymes known as ADP-ribosyltransferases (ARTs). Using nicotinamide adenine dinucleotide (NAD+) as the donor, ARTs covalently link single or multiple ADP-ribose moieties from NAD+ to the substrates, forming mono ADP-ribosylation or poly ADP-ribosylation (PARylation). Novel functions of ARTs and ADPribosylation have been revealed over the past few years. Here we summarize the current knowledge on ARTs and PARylation.

Aromatic stacking interactions arise from the attractive force between the π-electron clouds in the neighboring aromatic groups. The aromatic stacking is common between proteins and small molecules. The stacking interactions at the interfaces of proteins and other macromolecules are relatively rare. However it contributes to a significant portion of the stabilizing forces. In the proteinprotein complexes, aromatic interactions are involved in the protein oligomerization, such as dimer, trimer and tetramer formation. Also, aromatic residues can bind to nanoparticles through stacking interactions which offer them stronger affinity than other residues. These interactions play crucial roles in proteinnanoparticle conjugation. In the protein-nucleotide complexes, the specific recognitions are realized through stacking interactions between aromatic residues and the bases in the nucleotides. Many nucleoproteins use aromatic stacking to recognize binding site on DNA or RNA. Stacking interactions are involved in the process of mismatch repair, strand separation, deadenylation, degradation and RNA cap binding. They are proved to be important for the stability of complexes. The aromatic stacking is also the underlying reasons of many fatal diseases such as Alzheimer, cancer and cardiovascular diseases. The chemicals that can block the stacking interactions could have potential pharmaceutical values. In this review, we summarize recent finding regarding the functions of aromatic stacking interactions in the protein-macromolecule complexes. Our aim is to understand the mechanisms underlying the stacking-mediated complex formation and facilitate the development of drugs and other bio-products.

It is now well established that the protein folding reaction proceeds via accumulation of various intermediate states. Osmolytes, besides their role in protein stabilization, have also been shown to possess the ability of inducing tremendous affects on these protein folding intermediates, reshape the folding pathway and the energy landscape. The present article describes the advances made so far in understanding the effects of organic osmolytes on the folding intermediates and pathways. The ability of osmolytes to rescue disease causing mutations in proteins by inducing proper folding into functionally active form is also discussed. Finally, some future directions are described.

Serine proteases and their natural inhibitors have long been served as excellent models for studying (primary, secondary and tertiary) structure - activity relationships of biologically interacting proteins. As protein flexibility has been accepted as a “fourth dimension” of the protein structure, its contribution to the binding process has gained much interest. In this article we review extreme cases of serine protease interactions with canonical serine protease inhibitors that provide unique insights into the dynamics of protein- protein interactions. The major conclusions of our review article are: a) taxon-specific inhibitory effects of two highly homologous protease inhibitors from Schistocerca gregaria (SGCI and SGTI), as investigated by H/D exchange experiments and NMR spectroscopy, are due to their differential flexibilities, b) stabilities of some protease and inhibitor complexes, the wide-spread and increased flexibility of some segments in the protein-protein complexes, as studied by X-ray crystallography and NMR-spectroscopy, appear to be proportional to the physical stability of the complex.

Integrins regulate diverse functions in cancer pathology and in tumor cell development and contribute to important processes such as cell shape, survival, proliferation, transcription, angiogenesis, migration, and invasion. A number of snake venom proteins have the ability to interact with integrins. Among these are the disintegrins, a family of small, non-enzymatic, and cysteine-rich proteins found in the venom of numerous snake families. The venom proteins may have a potential role in terms of novel therapeutic leads for cancer treatment. Disintegrin can target specific integrins and as such it is conceivable that they could interfere in important processes involved in carcinogenesis, tumor growth, invasion and migration. Herein we present a survey of studies involving the use of snake venom disintegrins for cancer detection and treatment. The aim of this review is to highlight the relationship of integrins with cancer and to present examples as to how certain disintegrins can detect and affect biological processes related to cancer. This in turn will illustrate the great potential of these molecules for cancer research. Furthermore, we also outline several new approaches being created to address problems commonly associated with the clinical application of peptide-based drugs such as instability, immunogenicity, and availability.

The sactibiotics are a recently designated subclass of bacteriocins that contain characteristic cysteine sulphur to α -carbon linkages mediated through post-translational modifications. They are a relatively small subclass of bacteriocins compared to the most thoroughly studied lantibiotics. The sactibiotics that have been extensively studied thus far are thuricin CD, subtilosin A, thurincin H, and propionicin F. Despite their recent discovery, there have already been significant advances made in the study of sactibiotics, most notably the discovery of the narrow spectrum anti-Clostridium difficile sactibiotic, thuricin CD. In addition, scientists have gained insights into the mechanisms of action of the sactibiotic subtilosin A, which targets Listeria monocytogenes, Gardnerella vaginalis, and other pathogens. Also, the development of heterologous host systems and homologous expression and site-directed mutagenesis systems for the sactibiotic thurincin H have opened up many opportunities for further studies on this sactibiotic. These and other recent studies concerning the molecular biology, 3D structural elucidation, mode of action, self-protection mechanisms, and antimicrobial spectrum of the sactibiotic subgroup of bacteriocins are discussed in this review.

Enhancer of Zeste Homolog 2 (EZH2) is the core component of the polycomb repressive complex 2 (PRC2), possessing the enzymatic activity in generating di/tri-methylated lysine 27 in histone H3. EZH2 has important roles during early development, and its dysregulation is heavily linked to oncogenesis in various tissue types. Accumulating evidences suggest a remarkable therapeutic potential by targeting EZH2 in cancer cells. The first part reviews current strategies to target EZH2 in cancers, and evaluates the available compounds and agents used to disrupt EZH2 functions. Then we provide insight to the future direction of the research on targeting EZH2 in different cancer types. We comprehensively discuss the current understandings of the 1) structure and biological activity of EZH2, 2) its role during the assembling of PRC2 and recruitment of other protein components, 3) the molecular events directing EZH2 to target genomic regions, and 4) post-translational modification at EZH2 protein. The discussion provides the basis to inspire the development of novel strategies to abolish EZH2-related effects in cancer cells.