Current Protein and Peptide Science - Volume 14, Issue 2, 2013

Lanthipeptides are ribosomally synthesized and posttranslationally modified peptides produced by microorganisms. The name lanthipeptide is derived from lanthionine, a thioether–bridged amino acid installed by dedicated modification enzymes. Serines and threonines are dehydrated and subsequently coupled to cysteines, thus forming intramolecular lanthionine rings. A well–known subclass of lanthipeptides are lantibiotics: lanthipeptides with antimicrobial activity. The lantibiotic nisin is applied worldwide in the food industry to prevent food spoilage. This review focuses on lanthipeptide leader peptides, which have a crucial and central role in lanthipeptide biosynthesis. Lanthipeptide leader peptides are present at the N–terminus within precursor lanthipeptides. Intriguingly, a single leader peptide can interact with highly different modifying enzyme(s) (domains) and furthermore induce export out of the cell via a dedicated export protein. Eventually the leader peptide is cleaved off by a leader peptidase, either extracellularly or intracellularly as part of the transporter. Recent exciting mechanistic and engineering studies ignited the unraveling of the fascinating interactions of lanthipeptide leader peptides with the lanthipeptide modification enzymes and transporters. The biosynthesis of at least some lanthipeptides is performed by a highly flexible enzyme system. Novel lantibiotics can be synthesized by fusing lanthipeptide leader peptides to completely different silent lantibiotics obtained by genome mining. Moreover, the fusion of leader peptides to the N–terminus of medically and economically important therapeutic peptides has resulted in lanthioninestabilized therapeutics with enhanced bioavailability and optimized receptor interaction.

Autophagy and endocytosis are two evolutionarily conserved catabolic processes that comprise vesicle trafficking events for the clearance of the sequestered intracellular and extracellular cargo. Both start differently but end in the same compartment, the lysosome. Mounting evidences from the last years have established the involvement of proteins sensitive to intracellular Ca2+ in the control of the early autophagic steps and in the traffic of autophagic, endocytic and lysosomal vesicles. However, this knowledge is based on dispersed outcomes that do not set up a consensus model of the Ca2+–dependent control of autophagy and endocytosis. Here, we will provide a critical synopsis of insights from the last decade on the involvement of Ca2+–sensor proteins in the activation of autophagy and in fusion events of endocytic vesicles, autophagosomes and lysosomes.

Defining the minimal protein determinants of enzymic reactions, biological interactions, and immune recognition is at the core of biochemistry, pathology and therapeutics. Indeed, short peptide sequences are involved in physiological processes such as cell growth and apoptosis, and in pathological phenomena such as amyloid protein fibrillogenesis and tumor cell migration. An active peptide may exert more powerful activity than the entire parent protein and, in immunology, use of short peptides may improve immunotherapies and avoid the potential hazards of using full–length protein antigens. This review illustrates the concept that a peptide sequence only 5–residues long may be used as a basic functional unit in cell biology and immunology, underlines the crucial biological roles played by minisequences and emphasizes the multifold applications of short peptides as therapeutic agents.

Intra–molecular interactions within complex systems play a pivotal role in the biological function. They form a major challenge to computational structural proteomics. The network paradigm treats any system as a set of nodes linked by edges corresponding to the relations existing between the nodes. It offers a computationally efficient tool to meet this challenge. Here, we review the recent advances in the use of network theory to study the topology and dynamics of protein– ligand and protein–nucleic acid complexes. The study of protein complexes networks not only involves the topological classification in term of network parameters, but also reveals the consistent picture of intrinsic functional dynamics. Current dynamical analysis focuses on a plethora of functional phenomena: the process of allosteric communication, the binding induced conformational changes, prediction and identification of binding sites of protein complexes, which will give insights into intra–protein complexes interactions. Furthermore, such computational results may elucidate a variety of known biological processes and experimental data, and thereby demonstrate a huge potential for applications such as drug design and functional genomics. Finally we describe some web–based resources for protein complexes, as well as protein network servers and related bioinformatics tools.

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Despite several advances, little is known about GBM–specific aberrant signalling processes. The hedgehog (Hh) signalling pathway plays a central role in GBM pathogenesis and tumor progression. Its activation is mediated by sonic hedgehog (Shh), which binds to its receptor patched, PTCH, promoting Gli1 activation. Gli1 is a member of the Kruppel family of zinc finger transcription factors. Hh-Gli1 axis controls glioma stem cells (GSCs) behaviour, which is essential to GBM chemoand radioresistance. Thus, Gli1 modulates the expression of stemness genes and the self–renewal of CD133+ GSCs. The activation of Hh-Gli1 in GSCs seems to be dependent on the insulin–like growth factor (IGF) signaling, which also contributes to intrinsic and acquired resistance of GSCs to temozolomide (TMZ). Beyond Hh signals, Gli1 activity is also regulated by several elements, including Ras, Myc, Akt, p53 and PTEN. Recently, a truncated variant of Gli1 (tGli1) has been demonstrated to gain the ability to regulate expression of genes that are not modulated by Gli1, such as the migration-invasion–associated CD24 or the human vascular endothelial growth factor–A (VEGF–A), leading to their upregulation. This review will summarize the role of Gli proteins in GBM tumorigenesis and their potential impact on GBM therapy and treatment resistance.

Conformational Protein Diseases (CPDs) comprise over forty clinically and pathologically diverse disorders in which specific altered proteins accumulate in cells or tissues of the body. The most studied are Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, inclusion body myopathy, and the systemic amyloidoses. They are characterised by three dimensional conformational alterations, which are often rich in β- structure. Proteins in this non-native conformation are highly stable, resistant to degradation, and have an enhanced tendency to aggregate with like protein molecules. The misfolded proteins can impart their anomalous properties to soluble, monomeric proteins with the same amino acid sequence by a process that has been likened to seeded crystallization. However, these potentially pathogenic proteins also have important physiological actions, which have not completely characterized. This opens up the question of what process transforms physiological actions into pathological actions and most intriguing, is why potentially dangerous proteins have been maintained during evolution and are present from yeasts to humans. In the present paper, we introduce the concept of mis–exaptation and of mis–tinkering since they may help in clarifying some of the double edged sword aspects of these proteins. Against this background an original interpretative paradigm for CPDs will be given in the frame of the previously proposed Red Queen Theory of Aging.