Current Protein and Peptide Science - Volume 13, Issue 6, 2012

Humans are capable of sensing five basic tastes and of these, bitter taste sensation alone, is mediated by a large group of 25 cell surface proteins known as, bitter taste receptors (T2Rs). T2Rs belong to the G-protein coupled receptor (GPCR) superfamily. However, they share little homology with the large subfamily of Class A GPCRs. Very little progress has been made in understanding the dynamics of T2R activation, and in discovery of molecules that can block (bitter blockers) T2R activation. Only recently few structure-function studies focused on elucidating the ligand binding mechanisms of T2Rs have been published. Here we will discuss the roles of conserved amino acids in T2R structure-function, possible mechanisms of activation of T2Rs, and compare and contrast with the recent crystal structures of the Class A GPCRs.

Lantibiotics are ribosomally synthesised, post-translationally modified antimicrobial peptides produced by Gram positive bacteria, many which have broad-ranging antimicrobial activities. Lantibiotics have long been the subject of investigation with a view to their application as food preservatives or chemotherapeutic agents for clinical and veterinary medicine, while the associated biosynthetic machinery has been employed for peptide engineering purposes. However, although many lantibiotics are produced by generally regarded as safe or food-grade bacteria, it is increasingly apparent that a number of Gram positive pathogens, including strains of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus mutans, Streptococcus uberis and Enterococcus faecalis, also produce these compounds. It is proposed that production of these antimicrobials may provide the associated microorganisms with a competitive advantage when colonizing/infecting a host, thereby enhancing the virulence of the producing strain. Here we review the production of lantibiotics by these pathogens and discuss how their production may contribute to their disease-causing potential.

This review will summarize and discuss the current biological understanding of the motile eukaryotic flagellum, as posed out by recent advances enabled by post-genomics and proteomics approaches. The organelle, which is crucial for motility, survival, differentiation, reproduction, division and feeding, among other activities, of many eukaryotes, is a great example of a natural nanomachine assembled mostly by proteins (around 350-650 of them) that have been conserved throughout eukaryotic evolution. Flagellar proteins are discussed in terms of their arrangement on to the axoneme, the canonical “9+2” microtubule pattern, and also motor and sensorial elements that have been detected by recent proteomic analyses in organisms such as Chlamydomonas reinhardtii, sea urchin, and trypanosomatids. Such findings can be remarkably matched up to important discoveries in vertebrate and mammalian types as diverse as sperm cells, ciliated kidney epithelia, respiratory and oviductal cilia, and neuro-epithelia, among others. Here we will focus on some exciting work regarding eukaryotic flagellar proteins, particularly using the flagellar proteome of C. reinhardtii as a reference map for exploring motility in function, dysfunction and pathogenic flagellates. The reference map for the eukaryotic flagellar proteome consists of 652 proteins that include known structural and intraflagellar transport (IFT) proteins, less wellcharacterized signal transduction proteins and flagellar associated proteins (FAPs), besides almost two hundred unannotated conserved proteins, which lately have been the subject of intense investigation and of our present examination.

Scientists have united in a common search to sequence, store and analyze genes and proteins. In this regard, rapidly evolving bioinformatics methods are providing valuable information on these newly-discovered molecules. Understanding what has been done and what we can do in silico is essential in designing new experiments. The unbalanced situation between sequence-known proteins and attribute-known proteins, has called for developing computational methods or high-throughput automated tools for fast and reliably predicting or identifying various characteristics of uncharacterized proteins. Taking into consideration the role of viruses in causing diseases and their use in biotechnology, the present review describes the application of protein bioinformatics in virology. Therefore, a number of important features of viral proteins like epitope prediction, protein docking, subcellular localization, viral protease cleavage sites and computer based comparison of their aspects have been discussed. This paper also describes several tools, principally developed for viral bioinformatics. Prediction of viral protein features and learning the advances in this field can help basic understanding of the relationship between a virus and its host.

Skeletal muscle, the main protein reservoir in the body, is a tissue that exhibits high plasticity when exposed to changes. Muscle proteins can be mobilized into free amino acids when skeletal muscle wasting occurs, a process called skeletal muscle atrophy. This wasting is an important systemic or local manifestation under disuse conditions (e.g., bed rest or immobilization), in starvation, in older adults, and in several diseases. The molecular mechanisms involved in muscle wasting imply the activation of specific signaling pathways which ultimately manage muscle responses to modulate biological events such as increases in protein catabolism, oxidative stress, and cell death by apoptosis. Many factors have been involved in the generation and maintenance of atrophy in skeletal muscle, among them angiotensin II (Ang-II), the main peptide of renin-angiotensin system (RAS). Together with Ang-II, the angiotensin–converting enzyme (ACE) and the Ang-II receptor type 1 (AT-1 receptor) are expressed in skeletal muscle, forming an important local axis that can regulate its function. In many of the conditions that lead to muscle wasting, there is an impairment of RAS in a global or local fashion. At this point, there are several pieces of evidence that suggest the participation of Ang-II, ACE, and AT-1 receptor in the generation of skeletal muscle atrophy. Interestingly, the Ang-II participation in muscle atrophy is strongly ligated to the regulation of hypertrophic activity of factors such as insulin-like growth factor 1 (IGF-1). In this article, we reviewed the current state of Ang-II and RAS function on skeletal muscle wasting and its possible use as a therapeutic target to improve skeletal muscle function under atrophic conditions.

Cytotoxins (or cardiotoxins; CTs) are toxins from cobra venom characterized by the three-finger (TF) fold. CTs are on average 60-residue-long peptides, possessing as many as 4 disulfide bonds. The elements of antiparallel β-structure take origin from the hydrophobic core formed by the disulfides. The β-strands adopt the shape of the three loops, giving the name of the fold. While neurotoxins (NTs) - also TF proteins from snake venom - exert their effect through specific interactions with protein receptors, no specific protein target has been found for CTs. Unlike NTs, CTs are amphiphilic and cytotoxic against a variety of cells, including cancer ones. Thus, the hypothesis that the activity of CTs is caused by their interactions with lipid membranes is currently central. To understand molecular basis behind variations in toxicities of CTs highly homologous in their sequences, detailed knowledge of their structure and dynamics is required. The present review summarizes experimental and computational data on the spatial organization of CTs and their dynamics in various environments (aqueous solution, membranous milieus).

Membrane proteins play important roles in signal transduction across the cell membrane. Structural information for the membrane proteins is still limited due to many technical challenges. Membrane proteins containing a single α- helical transmembrane (TM) domain are very important in several pathways. Solution NMR spectroscopy is an important tool for the study of the structure of the TM domain of these types of proteins due to their small size. In this review, we summarize the importance of some single-span membrane proteins in signal transduction and the importance of understanding the structure of the TM domain. We discussed the current progress in the structural study of these types of proteins using solution NMR spectroscopy. We summarize the structures solved during last several years. The structures of the regulatory domain of the ion channels such as KCNE1, integrin and viral proteins such as the M2 channel are described. The binding interface of single TM-TM domains is discussed based on NMR structural studies. Strategies including sample preparation, detergent screening, and structural determination of single-span membrane protein are summarized. We also discuss the potential application of NMR spectroscopy to drug discovery of proteins with a single-span TM domain.