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The ubiquitin system plays an essential role in numerous cellular processes by controlling protein stability and function. An understanding of the mechanisms governing these processes is likely to allow the identification of novel targets for pharmacological intervention. This work covers the developments in this field.
This book, written by members of the European network PROTEOSTASIS, provides an up-to-date review of the research regarding protein homeostasis in health and disease. With new discoveries contributing to the increasing complexity of this topic, the book offers a detailed overview of the pathways regulating protein homeostasis, including autophagy and the ubiquitin protein family. Following a basic introduction, it explains how defects in protein homeostasis contribute to numerous pathologies, including cancer, neurodegeneration, inflammation and a number of rare diseases. In addition, it discusses, the role of protein homeostasis in cellular development and physiology. Highlighting the latest research in the field of protein homeostasis and its implications for various clinically relevant diseases, the book appeals to researchers and clinicians, while also offering a reference guide for scholars who are new to the field.
In recent years, powered by evolving technologies and experimental design, studies have better illuminated the regulating role of proteolytic enzymes across human development and pathologies. Proteolytic Signaling in Health and Disease provides an in-depth discussion of fundamental physiological and developmental processes regulated by proteases, from protein turnover and autophagy to antigen processing and presentation and major histocompatibility complex (MHC) molecules. Moving on from basic biology, international chapter authors examine a range of pathological conditions associated with proteolysis, including inflammation, wound healing, and cancer. Later chapters discuss the newly discovered network of connected events among proteases (and their inhibitors), the so-called 'protease web', and how best to study it. This book also empowers new research with up-to-date analytical methods and step-by-step protocols for studying proteolytic signaling events. - Examines biological events triggered by proteolytic enzyme activity across human development and pathologies - Discusses the role of proteolytic signaling in inflammation, wound healing, and cancer, among other disease types - Features methods and protocols supporting further study of proteolytic signaling events - Includes chapter contributions from international leaders in the field
The human ubiquitin proteasome system (UPS) is comprised of nearly 1000 proteins. Although originally identified as a mechanism of protein destruction, the UPS has numerous additional functions and mediates central signaling events in myriad processes involved in both cellular and organismal health and homeostasis. Numerous pathways within the UPS are implicated in disease, ranging from cancer to neurodegenerative diseases such as Parkinson's. The goal of this book is to deliver a collection of synopses of current areas of UPS research that highlights the importance of understanding the biology of the UPS to identify disease-relevant pathways, and the need to elucidate the molecular machinations within the UPS to develop methods for therapeutic modulation of these pathways.
Protein degradation has been identified as a major mechanism for the regulation of cellular functions. Not surprisingly, its deregulation is implied in almost any pathological condition. This book describes how aged proteins are eliminated during cell metabolism, how cell proliferation is regulated by protein degradation and how its deregulation can contribute to the development of cancer, how protein degradation is modified during normal and abnormal aging, in particular with regard to Alzheimer's disease and other degenerative diseases of the brain and central nervous system. Attempts aiming at correcting these pathologies by interfering with deviations of the normal pathway of protein degradation are also treated.
How to synthesize native and modified proteins in the test tube With contributions from a panel of experts representing a range of disciplines, Total Chemical Synthesis of Proteins presents a carefully curated collection of synthetic approaches and strategies for the total synthesis of native and modified proteins. Comprehensive in scope, this important reference explores the three main chemoselective ligation methods for assembling unprotected peptide segments, including native chemical ligation (NCL). It includes information on synthetic strategies for the complex polypeptides that constitute glycoproteins, sulfoproteins, and membrane proteins, as well as their characterization. In addition, important areas of application for total protein synthesis are detailed, such as protein crystallography, protein engineering, and biomedical research. The authors also discuss the synthetic challenges that remain to be addressed. This unmatched resource: Contains valuable insights from the pioneers in the field of chemical protein synthesis Presents proven synthetic approaches for a range of protein families Explores key applications of precisely controlled protein synthesis, including novel diagnostics and therapeutics Written for organic chemists, biochemists, biotechnologists, and molecular biologists, Total Chemical Synthesis of Proteins provides key knowledge for everyone venturing into the burgeoning field of protein design and synthetic biology.
SNARE proteins mediate the docking and/or fusion of the vesicle with the plasma membrane. However, it is not clearly understood how this process is regulated. In a search for potential SNARE regulators, we have identified a novel snare interacting protein, the septin CDCrel-1. Septins were first identified as filamentous proteins required for cytokinesis in yeast. However, in mammals little is known about their functions. I show here that cdcrel-1 is predominantly expressed in the brain where it associates with membranes via binding to syntaxin 1A. Wildtype CDCrel-1 transfected into HIT-T15 cells inhibits secretion while mutated forms of CDCrel-1 potentiate secretion, suggesting that cdcrel-1 may be regulating vesicle targeting and/or fusion events. I further map the CDCrel-1 domains important for syntaxin binding and investigate the ability of CDCrel-1 to bind to syntaxin when in various SNARE complexes. CDCrel-1 can bind syntaxin in a SNARE complex, but its binding is occluded by alpha-SNAP. This suggests that CDCrel-1 may act as a novel filamentous element, regulating the delivery and/or fusion of vesicles to the presynaptic membrane through its interaction with syntaxin and the 7S complex. The regulation of filaments may be via post-translational modifications. Indeed we have discovered a novel interaction between SUMO E3 PIAS proteins and CDCrel-1. The conjugation of SUMO to substrates is dependent upon an E1 and E2, whereas specificity is mediated by an E3. Although several SUMO-1 substrates have been characterized, conjugation solely by SUMO-2/3 has not been described. Here I describe the colocalization of CDCrel-1 with SUMO-2 and 3 but not SUMO-1. Transfection of SUMO-2/3 but not SUMO-1 causes a reorganization of CDCrel-1 distribution in CHO cells. Furthermore, CDCrel-1 sequesters the nuclear pool of SUMO-2/3 and of the E2 Ubc9 but not SUMO1 into the cytoplasm. Sumoylation of CDCrel-l is shown in vivo and putative SUMO modification sites on CDCrel-1 are investigated by deletion of lysine residues. These experiments strongly suggest that CDCrel-1 is sumoylated specifically by SUMO-2/3. Sumoylation of CDCrel-1 may therefore play a regulatory role in secretion and septin filament formation. Future work will be aimed at determining the functional significance of SUMO modified CDCrel-1.
This book covers important topics such as the dynamic structure and function of the 26S proteasome, the DNA replication machine: structure and dynamic function and the structural organization and protein–protein interactions in the human adenovirus capsid, to mention but a few. The 18 chapters included here, written by experts in their specific field, are at the forefront of scientific knowledge. The impressive integration of structural data from X-ray crystallography with that from cryo-electron microscopy is apparent throughout the book. In addition, functional aspects are also given a high priority. Chapter 1 is available open access under a Creative Commons Attribution 4.0 International License via link.springer.com.
Manganese in the diet is nutritionally essential for normal physiologic functioning. However, excessive exposure to manganese has been associated with developmental, neurodegenerative and other disorders. The book comprehensively covers the toxicology of manganese. Leading investigators provide perspectives from toxicology, neuroscience, nutrition, molecular biology and risk assessment disciplines and chapters cover the toxicokinetics, toxicodynamic interactions and health effects of manganese, as well as its potential role in neurodegenerative diseases. A large section devoted to health effects presents the latest research that associates manganese exposure to potential human diseases. Any scientists, health professional or regulator involved with metal exposure and toxicology should find this volume essential reading. Students and researchers in neurotoxicology will also find this book a useful reference.