Protein Reviews – serie

In Viral Membrane Proteins: Structure, Function, and Drug Design, Wolfgang Fischer summarizes the current structural and functional knowledge of membrane proteins encoded by viruses. In addition, contributors to the book address questions about proteins as potential drug targets. The range of information covered includes signal proteins, ion channels, and fusion proteins.This book has a place in the libraries of researchers and scientists in a wide array of fields, including protein chemistry, molecular biophysics, pharmaceutical science and research, bioanotechnology, molecular biology, and biochemistry.

The current year (2004) marks the Silver Anniversary of the discovery of the p53 tumor suppressor. The emerging ?eld ?rst considered p53 as a viral antigen and then as an oncogene that cooperates with activated ras in transforming primary cells in culture. Fueling the concept of p53 acting as a transforming factor, p53 expression was markedly elevated in various transformed and tumorigenic cell lines when compared to normal cells. In a simple twist of fate, most of the studies conducted in those early years inadvertently relied on a point mutant of p53 that had been cloned from a normal mouse genomic library. A bona ?de wild-type p53 cDNA was subsequently isolated, ironically, from a mouse teratocarcinoma cell line. A decade after its discovery, p53 was shown to be a tumor suppressor that protects against cancer. It is now recognized that approximately half of all human tumors arise due to mutations within the p53 gene. As remarkable as this number may seem, it signi?cantly underrepresents how often the p53 pathway is targeted during tumorigenesis. It is my personal view, as well as many in the p53 ?eld, that the p53-signaling pathway is corrupted in nearly 100% of tumors. If you are interested in understanding cancer and how it develops, you must begin by studying p53 and its pathway. After demonstrating that p53 functions as a tumor suppressor the ?eld exploded and p53 became a major focus of scientists around the world.

Gabriel Waksman Institute of Structural Molecular Biology, Birkbeck and University College London, Malet Street, London WC1E 7HX, United Kingdom Address for correspondence: Professor Gabriel Waksman Institute of Structural Molecular Biology Birkbeck and University College London Malet Street London WC1E 7H United Kingdom Email: g. waksman@bbk. ac. uk and g. waksman@ucl. ac. uk Phone: (+44) (0) 207 631 6833 Fax: (+44) (0) 207 631 6833 URL: http://people. cryst. bbk. ac. uk/?ubcg54a Gabriel Waksman is Professor of Structural Molecular Biology at the Institute of Structural Molecular Biology at UCL/Birkbeck, of which he is also the director. Before joining the faculty of UCL and Birkbeck, he was the Roy and Diana Vagelos Professor of Biochemistry and Molecular Biophysics at the Washington University School of Medicine in St Louis (USA). The rapidly evolving ?eld of protein science has now come to realize the ubiquity and importance of protein–protein interactions. It had been known for some time that proteins may interact with each other to form functional complexes, but it was thought to be the property of only a handful of key proteins. However, with the advent of hi- throughput proteomics to monitor protein–protein interactions at an organism level, we can now safely state that protein–protein interactions are the norm and not the exception.

This volume fills the gap in protein review and protocal literature while summarizing recent achievements in the understanding of the relationships between protein misfoldings, aggregation, and development of protein deposition disorders. It is devoted to the general questions of conformational disorders and includes discussion of involvement of such common factors as molecular chaperones, oxidative damage, proteasome, glycosoaminoglycans, serum amyloid protein P and several others in the development of different disorders. Some experimental techniques applicable for the visualization of protein deposition in vivo and in vitro are also present.

When I was invited to edit this volume, I wanted to take the opportunity to assemble reviews of different biophysical methodologies for protein interactions at a level suf?ciently detailed to understand how complex systems can be studied. There are several excellent introductory texts for biophysical methodologies, many with hands-on descriptions or embedded in general introductions to physical b- chemistry. The goal of the present volume was to present state-of-the-art reviews that do not necessarily enable the reader to carry out these techniques, but to gain a deep understanding of the biophysical observables, to stimulate creative thought on how the techniques may be applied to study a particular biological system, and to foster collaboration and multidisciplinary work. Reversible protein interactions involve noncovalent chemical bonds, pro- cing protein complexes with free energies not far from the order of magnitude of the thermal energy kT. As a consequence, they can be highly dynamic and may be controlled, for example, by protein expression levels and changes in the intracel- lar or microenvironment. Reversible protein complexes may have suf?cient stab- ity to be puri?ed for study, but frequently their short lifetime essentially limits their existence to solutions of mixtures of the binding partners in which they remain populated through dissociation and reassociation processes. To understand the function of such protein complexes, it is important to study their structure and dynamics.

The second volume continues to fill the gap in protein review and protocal literature while summarizing recent achievements in the understanding of the relationships between protein misfoldings, aggregation, and development of protein deposition disorders. The focus of Part B is the molecular basis of differential disorders.

Stressproteinssuchastheheatshockproteins(Hsp)andglucose-regulatedproteins (Grp) are front-line molecules in responses to cellular insult and play key roles in the viability of single cell organisms exposed to environmental stresses. However, the discovery of the roles of Hsp and Grp as molecular chaperones indicates much wider functions in the physiology of cells and organisms. It is now clear that some stress proteins are expressed constitutively and are key mediators of housekeeping protein folding in the day-to-day existence of the cell. The maturation of enzymes, transcriptionfactors,andcellsurfacereceptorsreliesonthesefunctionsofthestress proteins. In addition, the ability of stress proteins to manipulate the structures of target proteins has lent them cell regulatory properties over and above their role in folding the proteome and they play key roles in controlling signal transduction, cell death pathways and transcription. Recently, novel extracellular roles for the Hsp have also emerged as it has become apparent that the Hsp can escape from the cytoplasm of cells and play a signi?cant extracellular role in signaling to neighbor cells and in immunosurveiIlance. As might be expected with such key molecules, dysregulation of Hsp expression over time can lead to disastrous results in terms of the health of the organism. Under-expression of the Hsp is associated with advanced aging and neurodegeneration. Elevated expression is associated with malignant progression. We have aimed in this volume to indicate advances in each oftheseaspectsofstressproteinresearch,withchaptersrangingfrombasicstudies of the role of Hsp in protein folding to reviews examining the breakdown of stress protein regulation in disease. Stuart K.

Actin is a ubiquitous protein present in high concentrations in virtually all cells. It's assembly and disassembly is modulated by more than 100 actin-binding proteins. These interactions are essential for a variety of important cellular processes including cell division, gene expression and motility.There are scattered reports in the published literature citing relationships between actin, actin-binding proteins and disease. This volume brings this information together for the first time, with a focus on human disorders.This volume is relevant to a wide readership including cell biologists interested in understanding how structural and functional changes in proteins impact on the organism as a whole. Additionally, clinicians will be interested because the book explains the role of cytoskeletal proteins in various diseases, including cancer and immune system disorders.

The Discovery of Ribonuclease P and Enzymatic Activity of Its RNA Subunit Sydney Brenner and Francis H. C. Crick had a specific project in mind when they offered Sidney Altman a position in their group in 1969 to conduct postdoctoral research at the Medical Research Council Laboratory of Molecular Biology (LMB) in Cambridge, England. At the time, an intense international competition was on- ing in as many as a dozen labs to determine the three-dimensional structure of tRNA. At the LMB, Aaron Klug was attacking the structure by crystallographic analysis with Brian F. C. Clark providing large amounts of purified phenylalanine tRNA. (Eventually, Aaron announced his empirically determined 3-D structure of yeast phenylalanine tRNA, a structure that is generally common to tRNAs, due in part to several conserved, novel three-way nucleotide interactions. ) Concurrently, Michael Levitt, a Ph. D. student of Francis, was visually scrutinizing the cloverleaf secondary structure of the 14 tRNA sequences known at the time. Levitt was searching for nucleotide covariation in different parts of the molecules that were conserved in the 14 sequences known at the time. He identified a possible covariation of an apparent Watson-Crick pairing type between the residues at position 15 from the 5’ end of the tRNA and residue 48. This association implied these parts of the tRNA, namely the D loop containing residue 15 and the 5’ end of the T stem-adjoining residue 48, folded on one another in a tertiary structure shared by different tRNAs.

With the invitation to edit this volume, I wanted to take the opportunity to assemble reviews on different aspects of circadian clocks and rhythms. Although most c- tributions in this volume focus on mammalian circadian clocks, the historical int- duction and comparative clocks section illustrate the importance of various other organisms in deciphering the mechanisms and principles of circadian biology. Circadian rhythms have been studied for centuries, but only recently, a mole- lar understanding of this process has emerged. This has taken research on circadian clocks from mystic phenomenology to a mechanistic level; chains of molecular events can describe phenomena with remarkable accuracy. Nevertheless, current models of the functioning of circadian clocks are still rudimentary. This is not due to the faultiness of discovered mechanisms, but due to the lack of undiscovered processes involved in contributing to circadian rhythmicity. We know for example, that the general circadian mechanism is not regulated equally in all tissues of m- mals. Hence, a lot still needs to be discovered to get a full understanding of cir- dian rhythms at the systems level. In this respect, technology has advanced at high speed in the last years and provided us with data illustrating the sheer complexity of regulation of physiological processes in organisms. To handle this information, computer aided integration of the results is of utmost importance in order to d- cover novel concepts that ultimately need to be tested experimentally.

Stressproteinssuchastheheatshockproteins(Hsp)andglucose-regulatedproteins (Grp) are front-line molecules in responses to cellular insult and play key roles in the viability of single cell organisms exposed to environmental stresses. However, the discovery of the roles of Hsp and Grp as molecular chaperones indicates much wider functions in the physiology of cells and organisms. It is now clear that some stress proteins are expressed constitutively and are key mediators of housekeeping protein folding in the day-to-day existence of the cell. The maturation of enzymes, transcriptionfactors,andcellsurfacereceptorsreliesonthesefunctionsofthestress proteins. In addition, the ability of stress proteins to manipulate the structures of target proteins has lent them cell regulatory properties over and above their role in folding the proteome and they play key roles in controlling signal transduction, cell death pathways and transcription. Recently, novel extracellular roles for the Hsp have also emerged as it has become apparent that the Hsp can escape from the cytoplasm of cells and play a signi?cant extracellular role in signaling to neighbor cells and in immunosurveiIlance. As might be expected with such key molecules, dysregulation of Hsp expression over time can lead to disastrous results in terms of the health of the organism. Under-expression of the Hsp is associated with advanced aging and neurodegeneration. Elevated expression is associated with malignant progression. We have aimed in this volume to indicate advances in each oftheseaspectsofstressproteinresearch,withchaptersrangingfrombasicstudies of the role of Hsp in protein folding to reviews examining the breakdown of stress protein regulation in disease. Stuart K.

Actin is a ubiquitous protein present in high concentrations in virtually all cells. It's assembly and disassembly is modulated by more than 100 actin-binding proteins. These interactions are essential for a variety of important cellular processes including cell division, gene expression and motility.There are scattered reports in the published literature citing relationships between actin, actin-binding proteins and disease. This volume brings this information together for the first time, with a focus on human disorders.This volume is relevant to a wide readership including cell biologists interested in understanding how structural and functional changes in proteins impact on the organism as a whole. Additionally, clinicians will be interested because the book explains the role of cytoskeletal proteins in various diseases, including cancer and immune system disorders.

In Viral Membrane Proteins: Structure, Function, and Drug Design, Wolfgang Fischer summarizes the current structural and functional knowledge of membrane proteins encoded by viruses. In addition, contributors to the book address questions about proteins as potential drug targets. The range of information covered includes signal proteins, ion channels, and fusion proteins.This book has a place in the libraries of researchers and scientists in a wide array of fields, including protein chemistry, molecular biophysics, pharmaceutical science and research, bioanotechnology, molecular biology, and biochemistry.

This volume fills the gap in protein review and protocal literature while summarizing recent achievements in the understanding of the relationships between protein misfoldings, aggregation, and development of protein deposition disorders. It is devoted to the general questions of conformational disorders and includes discussion of involvement of such common factors as molecular chaperones, oxidative damage, proteasome, glycosoaminoglycans, serum amyloid protein P and several others in the development of different disorders. Some experimental techniques applicable for the visualization of protein deposition in vivo and in vitro are also present.

When I was invited to edit this volume, I wanted to take the opportunity to assemble reviews of different biophysical methodologies for protein interactions at a level suf?ciently detailed to understand how complex systems can be studied. There are several excellent introductory texts for biophysical methodologies, many with hands-on descriptions or embedded in general introductions to physical b- chemistry. The goal of the present volume was to present state-of-the-art reviews that do not necessarily enable the reader to carry out these techniques, but to gain a deep understanding of the biophysical observables, to stimulate creative thought on how the techniques may be applied to study a particular biological system, and to foster collaboration and multidisciplinary work. Reversible protein interactions involve noncovalent chemical bonds, pro- cing protein complexes with free energies not far from the order of magnitude of the thermal energy kT. As a consequence, they can be highly dynamic and may be controlled, for example, by protein expression levels and changes in the intracel- lar or microenvironment. Reversible protein complexes may have suf?cient stab- ity to be puri?ed for study, but frequently their short lifetime essentially limits their existence to solutions of mixtures of the binding partners in which they remain populated through dissociation and reassociation processes. To understand the function of such protein complexes, it is important to study their structure and dynamics.

The second volume continues to fill the gap in protein review and protocal literature while summarizing recent achievements in the understanding of the relationships between protein misfoldings, aggregation, and development of protein deposition disorders. The focus of Part B is the molecular basis of differential disorders.

Post-translational modifications serve many different purposes in several cellular processes such as gene expression, protein folding and transport to appropriate cell compartment, protein-lipid and protein-protein interactions, enzyme regulation, signal transduction, cell proliferation and differentiation, protein stability, recycling and degradation. Although several-hundred different modifications are known, the significance of many of them remains unknown. The enormous versatility of the modifications which frequently alter the physico-chemical properties of the respective proteins represents an extraordinary challenge in understanding their physiological role. Since essential cellular functions are regulated by protein modifications, an improvement of current understanding of their meaning might allow new avenues to prevent and/or alleviate human and animal diseases.

This book aims to cover the knowledge of protein folding accumulated from studies of disulfide-containing proteins, including methodologies, folding pathways, and folding mechanism of numerous extensively characterized disulfide proteins. Folding of Disulfide Proteins will be valuable supplementary reading for general biochemistry, biophysics, molecular biology, and cellular biology courses for graduate and undergraduate students. This book can also be used for specialized graduate-level biochemistry, biophysics, and molecular biology courses dedicated to protein folding as well as related biological problems and diseases.Will also be of interest to everybody interested in problems related to protein folding, and anyone who is interested in understanding the mechanism of protein misfolding and protein misfolding-related diseases.

Within the past two decades, extraordinary new functions for the nucleolus have begun to appear, giving the field a new vitality and generating renewed excitement and interest. These new discoveries include both newly-discovered functions and aspects of its conventional role. The Nucleolus is divided into three parts: nucleolar structure and organization, the role of the nucleolus in ribosome biogenesis, and novel functions of the nucleolus.

With the invitation to edit this volume, I wanted to take the opportunity to assemble reviews on different aspects of circadian clocks and rhythms. Although most c- tributions in this volume focus on mammalian circadian clocks, the historical int- duction and comparative clocks section illustrate the importance of various other organisms in deciphering the mechanisms and principles of circadian biology. Circadian rhythms have been studied for centuries, but only recently, a mole- lar understanding of this process has emerged. This has taken research on circadian clocks from mystic phenomenology to a mechanistic level; chains of molecular events can describe phenomena with remarkable accuracy. Nevertheless, current models of the functioning of circadian clocks are still rudimentary. This is not due to the faultiness of discovered mechanisms, but due to the lack of undiscovered processes involved in contributing to circadian rhythmicity. We know for example, that the general circadian mechanism is not regulated equally in all tissues of m- mals. Hence, a lot still needs to be discovered to get a full understanding of cir- dian rhythms at the systems level. In this respect, technology has advanced at high speed in the last years and provided us with data illustrating the sheer complexity of regulation of physiological processes in organisms. To handle this information, computer aided integration of the results is of utmost importance in order to d- cover novel concepts that ultimately need to be tested experimentally.

The Discovery of Ribonuclease P and Enzymatic Activity of Its RNA Subunit Sydney Brenner and Francis H. C. Crick had a specific project in mind when they offered Sidney Altman a position in their group in 1969 to conduct postdoctoral research at the Medical Research Council Laboratory of Molecular Biology (LMB) in Cambridge, England. At the time, an intense international competition was on- ing in as many as a dozen labs to determine the three-dimensional structure of tRNA. At the LMB, Aaron Klug was attacking the structure by crystallographic analysis with Brian F. C. Clark providing large amounts of purified phenylalanine tRNA. (Eventually, Aaron announced his empirically determined 3-D structure of yeast phenylalanine tRNA, a structure that is generally common to tRNAs, due in part to several conserved, novel three-way nucleotide interactions. ) Concurrently, Michael Levitt, a Ph. D. student of Francis, was visually scrutinizing the cloverleaf secondary structure of the 14 tRNA sequences known at the time. Levitt was searching for nucleotide covariation in different parts of the molecules that were conserved in the 14 sequences known at the time. He identified a possible covariation of an apparent Watson-Crick pairing type between the residues at position 15 from the 5’ end of the tRNA and residue 48. This association implied these parts of the tRNA, namely the D loop containing residue 15 and the 5’ end of the T stem-adjoining residue 48, folded on one another in a tertiary structure shared by different tRNAs.

Post-translational modifications serve many different purposes in several cellular processes such as gene expression, protein folding and transport to appropriate cell compartment, protein-lipid and protein-protein interactions, enzyme regulation, signal transduction, cell proliferation and differentiation, protein stability, recycling and degradation. Although several-hundred different modifications are known, the significance of many of them remains unknown. The enormous versatility of the modifications which frequently alter the physico-chemical properties of the respective proteins represents an extraordinary challenge in understanding their physiological role. Since essential cellular functions are regulated by protein modifications, an improvement of current understanding of their meaning might allow new avenues to prevent and/or alleviate human and animal diseases.

This book aims to cover the knowledge of protein folding accumulated from studies of disulfide-containing proteins, including methodologies, folding pathways, and folding mechanism of numerous extensively characterized disulfide proteins. Folding of Disulfide Proteins will be valuable supplementary reading for general biochemistry, biophysics, molecular biology, and cellular biology courses for graduate and undergraduate students. This book can also be used for specialized graduate-level biochemistry, biophysics, and molecular biology courses dedicated to protein folding as well as related biological problems and diseases.Will also be of interest to everybody interested in problems related to protein folding, and anyone who is interested in understanding the mechanism of protein misfolding and protein misfolding-related diseases.

Within the past two decades, extraordinary new functions for the nucleolus have begun to appear, giving the field a new vitality and generating renewed excitement and interest. These new discoveries include both newly-discovered functions and aspects of its conventional role. The Nucleolus is divided into three parts: nucleolar structure and organization, the role of the nucleolus in ribosome biogenesis, and novel functions of the nucleolus.

Gabriel Waksman Institute of Structural Molecular Biology, Birkbeck and University College London, Malet Street, London WC1E 7HX, United Kingdom Address for correspondence: Professor Gabriel Waksman Institute of Structural Molecular Biology Birkbeck and University College London Malet Street London WC1E 7H United Kingdom Email: g. waksman@bbk. ac. uk and g. waksman@ucl. ac. uk Phone: (+44) (0) 207 631 6833 Fax: (+44) (0) 207 631 6833 URL: http://people. cryst. bbk. ac. uk/?ubcg54a Gabriel Waksman is Professor of Structural Molecular Biology at the Institute of Structural Molecular Biology at UCL/Birkbeck, of which he is also the director. Before joining the faculty of UCL and Birkbeck, he was the Roy and Diana Vagelos Professor of Biochemistry and Molecular Biophysics at the Washington University School of Medicine in St Louis (USA). The rapidly evolving ?eld of protein science has now come to realize the ubiquity and importance of protein–protein interactions. It had been known for some time that proteins may interact with each other to form functional complexes, but it was thought to be the property of only a handful of key proteins. However, with the advent of hi- throughput proteomics to monitor protein–protein interactions at an organism level, we can now safely state that protein–protein interactions are the norm and not the exception.

The current year (2004) marks the Silver Anniversary of the discovery of the p53 tumor suppressor. The emerging ?eld ?rst considered p53 as a viral antigen and then as an oncogene that cooperates with activated ras in transforming primary cells in culture. Fueling the concept of p53 acting as a transforming factor, p53 expression was markedly elevated in various transformed and tumorigenic cell lines when compared to normal cells. In a simple twist of fate, most of the studies conducted in those early years inadvertently relied on a point mutant of p53 that had been cloned from a normal mouse genomic library. A bona ?de wild-type p53 cDNA was subsequently isolated, ironically, from a mouse teratocarcinoma cell line. A decade after its discovery, p53 was shown to be a tumor suppressor that protects against cancer. It is now recognized that approximately half of all human tumors arise due to mutations within the p53 gene. As remarkable as this number may seem, it signi?cantly underrepresents how often the p53 pathway is targeted during tumorigenesis. It is my personal view, as well as many in the p53 ?eld, that the p53-signaling pathway is corrupted in nearly 100% of tumors. If you are interested in understanding cancer and how it develops, you must begin by studying p53 and its pathway. After demonstrating that p53 functions as a tumor suppressor the ?eld exploded and p53 became a major focus of scientists around the world.

Following their own brilliant careers in haeme protein research, the outstanding scientists Jonathan and Beatrice Wittenberg continue to provide inspiration to the research community in the study of oxygen-binding proteins. Their research has provided the intellectual stimulus to bring together scientists from all over the world with the common goal of developing fascinating new ideas and performing innovative experiments. This book is dedicated to Jonathan’s and Bea’s lifetime careers. It further illuminates the facts and ideas which dot the paths they traced in Biochemistry and Physiology, elaborating on how these landmark achievements were made and how the haeme proteins community still refers to them. With the field of haeme protein science such a flourishing area, the contributors to this book predict Jonathan and Bea, having played such a seminal role, will continue to be key figures for quite some time to come.

Following their own brilliant careers in haeme protein research, the outstanding scientists Jonathan and Beatrice Wittenberg continue to provide inspiration to the research community in the study of oxygen-binding proteins. Their research has provided the intellectual stimulus to bring together scientists from all over the world with the common goal of developing fascinating new ideas and performing innovative experiments. This book is dedicated to Jonathan’s and Bea’s lifetime careers. It further illuminates the facts and ideas which dot the paths they traced in Biochemistry and Physiology, elaborating on how these landmark achievements were made and how the haeme proteins community still refers to them. With the field of haeme protein science such a flourishing area, the contributors to this book predict Jonathan and Bea, having played such a seminal role, will continue to be key figures for quite some time to come.

Prostate Cancer provides an up-to-date review of the biochemistry, molecular biology, and genetic changes in prostate cells that are the driving forces in the initiation and progression of cancer. It includes an overview by experts in the field of cell-cell interactions, including stem cells, reactive Stromal cells and membrane lipid rafts that are instrumental in the initiation and progression of prostate cancer.