Folding And Stability Studies On Amyotrophic Lateral Sclerosis Associated Apo Cu Zn Superoxide Dismutases
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Author | : Kenrick Allistair Vassall |
Publisher | : |
Total Pages | : 225 |
Release | : 2009 |
Genre | : |
ISBN | : |
Amyotrophic lateral sclerosis (ALS) is a debilitating, incurable, neurodegenerative disease characterized by degradation of motor neurons leading to paralysis and ultimately death in ~3-5 years. Approximately 10% of ALS cases have a dominant inheritance pattern, termed familial ALS (fALS). Mutations in the gene encoding the dimeric superoxide scavenger Cu, Zn superoxide dismutase (SOD), were found to be associated with ~20% of fALS cases. Over 110 predominantly missense SOD mutations lead to fALS by an unknown mechanism; however, it is thought that mutant SOD acquires a toxic gain of function. Mice as well as human post mortem studies have identified mutant SOD-rich aggregates in affected neurons, leading to the hypothesis that mutations in SOD increase the tendency of the protein to form toxic aggregates. SOD has a complex maturation process whereby the protein is synthesized in an apo or demetalated state, followed by formation of an intramolecular disulfide bond and binding of Zn2+ and Cu2+. Each of these post-translational modifications increases the stability of the protein. SOD has been shown to aggregate more readily from destabilized immature states, including the apo state both with and without the disulfide bond, highlighting the importance of these states. Thermal unfolding monitored by differential scanning calorimetry (DSC) and chemical denaturation monitored by optical spectroscopy were used to elucidate the folding mechanism and stability of both the apo SOD disulfide-intact and disulfide-reduced states. Chemically and structurally diverse fALS-associated mutants were investigated to gain insights into why mutant SODs may be more prone to misfold and ultimately aggregate. The mutations were introduced into a pseudo wild-type (PWT) background lacking free cysteines, resulting in highly reversible unfolding amenable to accurate thermodynamic analysis. Similarly to what was previously described for fully metallated (holo) SODs, chemical denaturation of the apo disulfide-intact SODs is well described by a 3-state dimer mechanism with native dimer, monomeric intermediate and unfolded monomer populated at equilibrium. Although removal of metals has a relatively small effect on the stability of the dimer interface, the stability of the monomer intermediate is dramatically reduced. Thermal unfolding of some disulfide-intact apo SOD mutants as well as PWT is well described by a 2-state dimer mechanism, while others unfold via a 3-state mechanism similar to chemical denaturation. All but one of the studied disulfide-intact apo mutations are destabilizing as evidenced by reductions in [Delta]G of unfolding. Additionally, several mutants show an increased tendency to aggregate in thermal unfolding studies through increased ratios of van't Hoff to calorimetric enthalpy (HvH/ Hcal ). The effects of the mutations on dimer interface stability in the apo disulfide-intact form were further investigated by isothermal titration calorimetry (ITC) which provided a quantitative measure of the dissociation constant of the dimer (Kd). ITC results revealed that disulfide-intact apo SOD mutants generally have increased Kd values and hence favor dimer dissociation to the less stable monomer which has been proposed to be a precursor to toxic aggregate formation. Reduction of the disulfide bond in apo SOD leads to marked destabilization of the dimer interface, and both thermal unfolding and chemical denaturation of PWT and mutants are well described by a 2-state monomer unfolding mechanism. Most mutations destabilize the disulfide-reduced apo SOD to such an extent that the population of unfolded monomer under physiological conditions exceeds 50%. The disulfide-reduced apo mutants show increased tendency to aggregate relative to PWT in DSC experiments through increased HvH /Hcal, low or negative change in heat capacity of unfolding and/or decreased unfolding reversibility. Further evidence of enhanced aggregation tendency of disulfide-reduced apo mutants was derived from analytical ultracentrifugation sedimentation equilibrium experiments that revealed the presence of weakly associated aggregates. Overall, the results presented here provide novel insights into SOD maturation and the possible impact of stability on aggregation.
Author | : Jorge Abelardo Rodriguez |
Publisher | : |
Total Pages | : 344 |
Release | : 2004 |
Genre | : |
ISBN | : |
Author | : Sandra M. Lynch |
Publisher | : |
Total Pages | : 84 |
Release | : 2005 |
Genre | : |
ISBN | : 9780542496882 |
Author | : Martin Henrik Maurer |
Publisher | : IntechOpen |
Total Pages | : 740 |
Release | : 2012-01-20 |
Genre | : Medical |
ISBN | : 9789533078069 |
Though considerable amount of research, both pre-clinical and clinical, has been conducted during recent years, Amyotrophic Lateral Sclerosis (ALS) remains one of the mysterious diseases of the 21st century. Great efforts have been made to develop pathophysiological models and to clarify the underlying pathology, and with novel instruments in genetics and transgenic techniques, the aim for finding a durable cure comes into scope. On the other hand, most pharmacological trials failed to show a benefit for ALS patients. In this book, the reader will find a compilation of state-of-the-art reviews about the etiology, epidemiology, and pathophysiology of ALS, the molecular basis of disease progression and clinical manifestations, the genetics familial ALS, as well as novel diagnostic criteria in the field of electrophysiology. An overview over all relevant pharmacological trials in ALS patients is also included, while the book concludes with a discussion on current advances and future trends in ALS research.
Author | : Peter Basile Stathopulos |
Publisher | : Library and Archives Canada = Bibliothèque et Archives Canada |
Total Pages | : 708 |
Release | : 2005 |
Genre | : |
ISBN | : 9780494029541 |
Author | : Stephen J. Lippard |
Publisher | : University Science Books |
Total Pages | : 444 |
Release | : 1994 |
Genre | : Medical |
ISBN | : 9780935702729 |
The use of unnatural metals - which have been introduced into human biology as diagnostic probes and drugs - is another active area of tremendous medical significance.
Author | : Yutaka Ito |
Publisher | : Royal Society of Chemistry |
Total Pages | : 322 |
Release | : 2019-12-09 |
Genre | : Science |
ISBN | : 1839160934 |
In-cell NMR spectroscopy is a relatively new field. Despite its short history, recent in-cell NMR-related publications in major journals indicate that this method is receiving significant general attention. This book provides the first informative work specifically focused on in-cell NMR. It details the historical background of in-cell NMR, host cells for in-cell NMR studies, methods for in-cell biological techniques and NMR spectroscopy, applications, and future perspectives. Researchers in biochemistry, biophysics, molecular biology, cell biology, structural biology as well as NMR analysts interested in biological applications will all find this book valuable reading.
Author | : Cláudio M. Gomes |
Publisher | : CRC Press |
Total Pages | : 302 |
Release | : 2016-04-19 |
Genre | : Medical |
ISBN | : 1439809658 |
The role of metal ions in protein folding and structure is a critical topic to a range of scientists in numerous fields, particularly those working in structural biology and bioinorganic chemistry, those studying protein folding and disease, and those involved in the molecular and cellular aspects of metals in biological systems. Protein Folding an
Author | : Mikael Hörnqvist |
Publisher | : Cambridge University Press |
Total Pages | : 323 |
Release | : 2004-11-25 |
Genre | : Political Science |
ISBN | : 1139456342 |
Mikael Hörnqvist challenges us to rethink the overall meaning and importance of Machiavelli's political thinking. Machiavelli and Empire combines close textual analysis of The Prince and The Discourses with a broad historical approach, to establish the importance of empire-building and imperial strategy in Machiavelli's thought. The primary context of Machiavelli's work, Hörnqvist argues, is not the mirror-for-princes genre or medieval and Renaissance republicanism in general, but a tradition of Florentine imperialist republicanism dating back to the late thirteenth-century, based on the twin notions of liberty at home and empire abroad. Weaving together themes and topics drawn from contemporary Florentine political debate, Medicean ritual and Renaissance triumphalism, this study explores how Machiavelli in his chancery writings and theoretical works promoted the long standing aspirations of Florence to become a great and expanding empire, modelled on the example of the ancient Roman republic. This is a distinctive and important work.
Author | : Toshiyuki Fukada |
Publisher | : Springer Nature |
Total Pages | : 412 |
Release | : 2019-12-13 |
Genre | : Medical |
ISBN | : 9811505578 |
This book, now in an extensively revised second edition, describes the crucial role of zinc signaling in biological processes on a molecular and physiological basis. Global leaders in the field review the latest knowledge, including the very significant advances in understanding that have been achieved since publication of the first edition. Detailed information is provided on all the essentials of zinc signaling, covering molecular aspects and the roles of zinc transporters, the zinc sensing receptor, and metallothioneins. Detection techniques for zinc signals, involving genetically encoded and chemical probes, are also described. The critical contributions of the zinc signal in maintaining health and the adverse consequences of any imbalance in the signal are then thoroughly addressed. Here, readers will find up-to-date information on the significance of the zinc signal in a wide range of conditions, including cardiovascular disorders, neurodegenerative diseases, diabetes, autoimmune diseases, inflammatory conditions, skin disease, osteoarthritis, and cancer. The book will be of value for researchers, clinicians, and advanced students.