Download or read book Role of the C terminal Region of Cardiac Troponin I in Thin Filament Regulation written by Zhiqun Zhou and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Abnormal contraction and/or relaxation of cardiac muscle can cause heart diseases, heart failure, or even death. Contractile behavior of cardiac muscle is regulated by a series of Ca2+-induced structural transitions of troponin. These Ca2+-induced structural transitions regulate the alternating interactions between myosin heads and actin, but the detailed mechanisms of the regulation remain unclear. The long-term goal is to uncover the molecular basis of the Ca2+-induced protein structure transitions that underlie the regulation of cardiac function and to understand how these are altered in the diseased state. The overall objective of this work is to define the detailed dynamic and kinetic mechanisms of Ca2+-induced cardiac thin filament activation/deactivation, specific C-terminal of cTnI in the reconstituted preparations and determine how it is affected by troponin phosphorylation and cardiomyopathy mutations found in cTnI. The central hypothesis of this work is that different functional regions of cTnI play different roles in regulating dynamics and kinetics of the thin filament. We tested our hypothesis by monitoring the structural dynamic and kinetic transitions using various fluorescence spectroscopic techniques. Specific Aim 1 was designed to determine the dynamic and kinetic of each function region of C terminal of cTnI within reconstituted thin filament. Specific Aim 2 was designed to determine the structural and kinetic effects of selected hypertrophy cardiomyopathy (HCM) related cTnI mutations on the regulatory switching activity of cTnI within reconstituted thin filament. Specific Aim 3 was designed to determine the structural and kinetic effects of PKC-dependent phosphomimetic mutations on C-cTnI within reconstituted thin filament. Our findings reveal that each functional region of C-terminal of cTnI plays unique dynamic and kinetic roles in regulating Ca2+-induced crossbridge attachment/detachment; HCM-related mutations and PKC phosphomimetic mutations on C-cTnI modulate the dynamic and kinetic transitions in unique and various ways; the fly casting mechanism that normally underlies deactivation is preserved in spite of mutations. The positive impact of this work is that it provides a more detailed understanding of the mechanism of cardiac muscle regulation, which is important for understanding the molecular basis of disease-causing mutations and the possibility of rational therapeutic intervention.

Download or read book Role of the N terminal Region of Troponin T in Cardiac Muscle Contractile Activation written by Ranganath Mamidi and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Cardiac muscle contraction is the result of coordinated interactions between the contractile regulatory proteins of the thick and thin filaments, and a detailed understanding of how they interact is central to advancing treatments for human heart diseases. Coordinated interactions between the regulatory proteins mediate Ca2+-, crossbridge (XB)-, and sarcomere length (SL)-dependent cardiac contractile activation. The thick filaments contain myosin, while the thin filament proteins include actin, tropomyosin (Tm), cardiac troponin C, cardiac troponin I, and cardiac troponin T (cTnT). cTnT is a key player in cardiac contraction since it interacts with all other proteins on the thin filament. In particular, cTnT has an N-terminal end that extends into the neighboring structural unit (SU; 7actin:1Tm:1Tn), indicating that this region has a cardiac-specific functional role. However, there is a lack of knowledge regarding the role of the N-terminal end in cardiac contraction. Thus, the overall objective of this dissertation is to determine the role of specific regions in the N-terminal end of cTnT in regulating Ca2+-, XB-, and SL-mediated cardiac contraction. The central hypothesis is that the functional role of specific regions in the N-terminal end of cTnT is modulated by shifts in the isoforms of Tm and myosin heavy chain (MHC). We tested our hypothesis by deleting specific regions in the N-terminal end of cTnT and measuring the contractile function in fibers reconstituted with the cTnT variants. Specific Aim 1 was designed to determine the cardiac-specific role of the N-terminal end of cTnT. Specific Aim 2 was designed to determine how changes in Tm affect the role of the N-terminal end of cTnT. Specific Aim 3 was designed to determine how shifts in MHC isoforms affect the role of the N-terminal end of cTnT. Our findings reveal that specific regions of in the N-terminal end of cTnT have distinct functional impact, and that changes in Tm and MHC modify the impact of the N-terminal end of cTnT in cardiac contraction. New insights from our study will have a positive impact because they further our understanding regarding the role of the N-terminal end of cTnT under physiological and diseased states.

Download or read book In Vitro and in Situ Fluorescence Spectroscopic Investigations of the Structural Basis of the Thin Filament Regulatory Switching Activity of Cardiac Troponin written by Daniel Carl Rieck and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Fluorescence spectroscopic methods have been used in three primary studies to probe the role of the N-terminal domain of cardiac troponin C (N-cTnC) and the C-terminal domain of cardiac troponin I (C-cTnI) in the molecular mechanism underlying thin filament regulation. In the first study, we determined that the behavior of single fluorophore anisotropy probes attached to the inhibitory region of cTnI (cTnI-Ir), the switch region (cTnI-Sr), or the mobile domain (cTnI-Md) arises from the conformational dynamics of the labeled protein region. Our results from subsequent anisotropy experiments indicated that the N-cTnC--cTnI-Sr interaction counterbalances the cTnI-Md-actin and cTnI-Ir-actin interactions, such that cTnI-Sr pulls C-cTnI toward N-cTnC, whereas cTnI-Ir and cTnI-Md pull C-cTnI in the opposite direction toward actin. Thin filament activation and deactivation are thus caused by shifts in the balance between these protein-protein interactions induced by Ca2+ and myosin binding or dissociation events. In the second study, we successfully implemented our steady-state Forster resonance energy methods in the in situ molecular environment of skinned cardiac muscle fibers. We determined that strong actomyosin interactions associated with cycling cross-bridges enhance the Ca2+ sensitivity of the thin filament by exerting a stabilizing effect on N-cTnC opening that is likely indirect and mediated through cTnI. We also discovered that while this Ca2+ sensitizing effect of strong actomyosin interactions is allosterically transmitted between thin filament regulatory units, cooperativity itself is intrinsic to the thin filament ultrastructure such that strong actomyosin interactions are not needed to achieve cooperative Ca2+-dependent thin filament activation. Finally, in the third study, which generated preliminary data for a grant proposal, by preparing a truncation mutant of cTnI wherein the cTnI-Md had been removed and then incorporating this mutant into skinned muscle fibers, we determined that cTnI-Md plays important roles in thin filament cooperativity and the basal inhibition of force generation at diastolic Ca 2+ levels. Additionally, we used time-resolved FRET measurements to study the relationship between thin filament activation, cross-bridge binding state, and sarcomere length. We found compelling evidence that myofilament length dependent activation involves the modulation of cross-bridge feedback activation of the thin filament by changes in sarcomere length.

Download or read book Myofibrillogenesis written by Dipak K. Dube and published by Springer Science & Business Media. This book was released on 2001-10-19 with total page 304 pages. Available in PDF, EPUB and Kindle. Book excerpt: Myofibrillogenesis has been studied extensively over the last 100 years. Until recently, we have not had a comprehensive understanding of this fundamental process. The emergence of new technologies in molecular and cellular biology, combined with classical embryology, have started to unravel some of the complexities of myofibril assembly in striated muscles. In striated muscles, the contractile proteins are arranged in a highly ordered three dimensional lattice known as the sarcomere. The assembly of a myofibril involves the precise ordering of several proteins into a linear array of sarcomeres. Multiple isoforms in many of these proteins further complicate the process, making it difficult to define the precise role of each component. This volume has been compiled as a comprehensive reference on myofibrillogenesis. In addition, the book includes reviews on myofibrillar disarray under various pathological conditions, such as familial hypertrophic cardiomyopathy (FHC), and incorporates a section on the conduction system in the heart. Much of the information in this volume has not been described elsewhere. Presented in a manner to be of value to students and teachers alike, "Myofibrillogenesis" will be an invaluable reference source for all in the fields of muscle biology and heart development.

Download or read book Cardiac Markers written by Alan H. B. Wu and published by Springer Science & Business Media. This book was released on 2003-06-12 with total page 460 pages. Available in PDF, EPUB and Kindle. Book excerpt: In this greatly enlarged and thoroughly updated edition of his much praised Cardiac Markers, Alan Wu and his contributors focus on the use of markers in the practice of cardiology and-for the first time-on the use of natriuretic peptides for congestive heart failure. Here, leading international authorities in clinical chemistry and laboratory medicine, cardiology, emergency medicine, and the in vitro diagnostics industry describe the state-of-the-art uses of cardiac markers when treating coronary artery disease, and discuss in detail how they may be optimally used in a clinical setting. Comprehensive and cutting-edge, Cardiac Markers, Second Edition offers physicians a complete guide to the use of cardiac markers in clinical practice and clinical laboratorians a close-up view of the new markers now becoming standard.

Download or read book Functional Significance of the Mobile Domain of Cardiac Troponin I written by Nazanin Bohlooli Ghashghaee and published by . This book was released on 2018 with total page 156 pages. Available in PDF, EPUB and Kindle. Book excerpt: Protein-protein interactions between the thick and thin filaments and among thin filament proteins, particularly the troponin complex, play a vital role in regulation of cardiac contractility. As Ca2+ binds to troponin C (cTnC) at the beginning of systole, the C-terminus of troponin I (cTnI) plays an important role in switching cTnI from interacting with actin to primarily interacting with the N-domain of cTnC (N-cTnC) which is necessary for contraction. Among the thin filament proteins, cTnI is a key component of Ca2+ activation and is known to be involved in length dependent activation (LDA) of cardiac contractility. Although important information has been uncovered regarding the role of the mobile domain of cTnI (cTnI-MD) in cardiac contractility, the significance of cTnI-MD in the kinetics of cross-bridge cycling, the structural transitions within the thin filament, and tension development is yet to be determined. To characterize the functional significance of cTnI-MD in LDA and the regulation of actomyosin binding we developed three Specific Aims in this study. Aim 1 was designed to study the potential interaction between troponin and myosin and its effect on the ATPase activity of myosin and to identify if the C-terminus of cTnI is involved in a troponin--myosin interaction. Aim 2 was designed to study the role of cTnI-MD in modulating the effects of sarcomere length and strong cross-bridges on Ca2+-induced structural transitions of N-cTnC in reconstituted rat papillary muscle fibers. Aim 3 was designed to study the role of cTnI-MD in modulating the length-dependent tension-pCa relationship and the kinetics of cross-bridge cycling in reconstituted rat papillary muscle fibers. Our findings revealed truncation of cTnI-MD changes the relative contribution of the thick and thin filament to LDA. Our results show that truncating the entire cTnI-MD disrupts the length-dependent thin filament regulation which involves greater N-cTnC opening, Ca2+-sensitivity, and cooperativity of contraction at longer SL while the length-dependent increase in maximal tension is preserved. This study is anticipated to significantly contribute to our understanding of the underlying mechanisms of cardiac contractility which may help the development of cardiac therapeutics in future.

Download or read book Tropomyosin written by Peter Gunning and published by Springer Science & Business Media. This book was released on 2009-09-30 with total page 323 pages. Available in PDF, EPUB and Kindle. Book excerpt: A recent review of one of my grant applications commented on the ‘rediscovery of tropomyosin’. I was tempted to write back in my rebuttal to the reviewer that I didn’t realise it had been lost. Uncharacteristic maturity prevailed and I resisted the temptation, but I was struck by the underlying observation that research on the str- ture and function of tropomyosin has been somewhat invisible, particularly in terms of the cytoskeleton isoforms. So, how can it be that one of the two major components of the actin filament has been so thoroughly overlooked? I suspect that the answer is disappointingly pedestrian. Whereas the biochemistry of the 1980s revealed the potential of tropomyosin isoforms to diversify the function of actin filaments, the subsequent disenchantment with isoform biology in general in the 1990s inhibited growth of this field. With the development of more sophisticated experimental - proaches we are now seeing a growing realisation of the importance of tropomyosin in regulating actin filaments beyond its pivotal role in muscle contraction. The opportunity to edit this book came at a time when we had written several reviews on different aspects of tropomyosin function and I had just finished the background reading for a comprehensive review of tropomyosin biology. I realised that the field was simply beyond the capacity of any one person to do the field j- tice.

Download or read book Disorders of Voluntary Muscle written by George Karpati and published by Cambridge University Press. This book was released on 2001-07-12 with total page 800 pages. Available in PDF, EPUB and Kindle. Book excerpt: Rewritten and redesigned, this remains the one essential text on the diseases of skeletal muscle.

Download or read book Role of Protein Protein Interactions in Proper Formation and Function of Cardiac Thin Filaments written by Thu Ngoc Anh Ly and published by . This book was released on 2018 with total page 231 pages. Available in PDF, EPUB and Kindle. Book excerpt: In striated muscle, actin-based thin filaments and myosin-based thick filaments are organized into basic contractile units called sarcomeres. Tropomyosin (Tpm), a two-stranded coiled-coil protein, assembles in a head-to-tail manner to extend along the thin filament. Tpm stabilizes the thin filament and, along with the troponin complex (Tn), regulates Ca2+-dependent actomyosin interactions which are molecular prerequisites for muscle contraction. Thin filaments are polar with the pointed ends directed toward the M band and the barbed ends anchored to the Z disks. At the pointed end, the N-terminus of Tpm interacts with tropomodulin (Tmod) and leiomodin (Lmod). Tmod is an efficient pointed-end capping protein, whereas Lmod, its larger homologue, does not completely prevent elongation of the thin filament from the pointed end. The dissertation determines the arrangement and functional significance of Tpm- and actin-binding sites within the N-terminal region of Lmod2, a major Lmod isoform in cardiac muscle. We found that Lmod2 contains only one Tpm-binding site and binds to only one Tpm molecule. The N-terminal actin-binding site of Lmod2 is located within residues 43-90, with additional actin-binding interactions within residues 124-201. We found that the N-terminal Tpm- and actin-binding sites are important for Lmod2's assembly to the pointed end in cardiomyocytes where it acts as a leaky cap to regulate actin dynamics. The dissertation investigates effects of cardiomyopathy-linked mutations K15N and R21H in Tpm1.1, a striated muscle Tpm isoform, on the Ca2+ -dependent regulation and pointed-end dynamics of cardiac thin filaments. We found that the K15N mutation, but not the R21H mutation, decreases the Ca2+ sensitivity of thin filaments and the rate of structural changes within cTn triggered by Ca2+ dissociation from cTn. The R21H mutation significantly destabilizes the structural integrity of Tpm1.1 near its N-terminus and reduces Tpm1.1's affinity for F-actin and Lmod2. The R21H mutation also affects the in vitro pointed-end capping ability of Lmod2 and changes how Lmod2 binds to the sides of F-actin. Our data suggest that the K15N mutation causes DCM mostly by altering the Ca 2+-dependent thin filament regulation, and one possible HCM-causing mechanism of the R21H mutation is through alteration of Lmod2's function.

Download or read book The Role of Cardiac Troponin T troponin I Interactions in Regulating Cardiac Function in Health and Disease written by Steven James Ford and published by . This book was released on 2012 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Alterations of cardiac contractile proteins are a known cause or consequence of heart disease; however, little is known about how particular alterations in cardiac contractile proteins affect contractile function. Highly-coordinated interactions between thin-filament regulatory proteins cardiac troponin C, cardiac troponin T (cTnT), cardiac troponin I (cTnI), and tropomyosin regulate cardiac muscle contraction. Force-generating myosin crossbridges (XBs) further regulate myofilament function by modulating thin-filament protein interactions that lead to contractile activation. cTnT interacts with all other proteins on the thin filament to regulate Ca2+-, sarcomere length (SL)-, and XB-dependent contractile activation. However, there is a lack of knowledge about the functional significance of the cardiac-specific structure of motifs involved in cTnT-cTnI interaction. The significance of this lack of knowledge is highlighted by the fact that structural alterations in and near regions of cTnT-cTnI interactions are associated with heart disease. Therefore, the overall objective of this dissertation is to determine how cTnT-cTnI interactions regulate Ca 2+- and SL-dependent activation and underlie contractile function of the heart in cardiac health and disease. The hypothesis of this research was that cardiac-specific structural interactions between helical regions of cTnT and cTnI play a regulatory role in cardiac-specific contractile regulation. We tested our hypothesis by measuring the contractile function and dynamics of cardiac muscle tissue containing variations of cTnT and cTnI within regions where these proteins are known to interact. Specific Aim 1 was designed to probe how cardiac-specific cTnT-cTnI interactions contribute to cardiac-specific contractile function. Specific Aim 2 was designed to determine how disease-related mutations within the cTnT-cTnI interface affect contractile function and examine how myosin XBs further influence the dysfunctional phenotype. In support of our hypotheses, we found that cardiac-specific interactions between cTnT and cTnI were important for cardiac-specific contractile function, and that disease-related mutations the regions of cTnT-cTnI interaction led to functional aberrations consistent with dysfunctional phenotypes seen in cardiac disease. This research is anticipated to significantly contribute to our knowledge of the underlying mechanisms of cardiac pump function and provide insights fundamental to the development of therapies for cardiac dysfunction due to heart disease.

Download or read book Essentials of Medical Biochemistry written by Chung Eun Ha and published by Academic Press. This book was released on 2011-01-28 with total page 600 pages. Available in PDF, EPUB and Kindle. Book excerpt: Expert biochemist N.V. Bhagavan’s new work condenses his successful Medical Biochemistry texts along with numerous case studies, to act as an extensive review and reference guide for both students and experts alike. The research-driven content includes four-color illustrations throughout to develop an understanding of the events and processes that are occurring at both the molecular and macrolecular levels of physiologic regulation, clinical effects, and interactions. Using thorough introductions, end of chapter reviews, fact-filled tables, and related multiple-choice questions, Bhagavan provides the reader with the most condensed yet detailed biochemistry overview available. More than a quick survey, this comprehensive text includes USMLE sample exams from Bhagavan himself, a previous coauthor. Clinical focus emphasizing relevant physiologic and pathophysiologic biochemical concepts Interactive multiple-choice questions to prep for USMLE exams Clinical case studies for understanding basic science, diagnosis, and treatment of human diseases Instructional overview figures, flowcharts, and tables to enhance understanding

Download or read book Anatomy Physiology written by Lindsay Biga and published by . This book was released on 2019-09-26 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: A version of the OpenStax text

Download or read book Molecular Biology of The Cell written by Bruce Alberts and published by . This book was released on 2002 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Molecular Anatomy of Cellular Systems written by I. Endo and published by Elsevier. This book was released on 2002-08-20 with total page 241 pages. Available in PDF, EPUB and Kindle. Book excerpt: In this book, the progress during the last ten years is reviewed and future plans outlined to realize and establish the concept of design in the biological sciences. Design is a leading concept as well as the principal motivation for the creation of artificial systems. A successful design generally requires that the structures and functions of the elements that constitute the system as well as the principles that determine how the elements cooperate together to create function be fully understood. These requirements have not been satisfied within the fields of biotechnology and medicine. Compared to the recent emergence of artificial systems, living organisms acquired their present day structures and functions through evolution over three to four billion years. Despite the fact that the design of living organisms is recorded in the DNA sequence, our understanding of the structures and functions of the elements that constitute living organisms is very limited. To fulfill the requirements, the following approaches were initiated under a ten-year project entitled "Biodesign Research". Firstly, we tried to isolate and characterize the functional elements that constitute the organelles of various organisms. Secondly, we tried to reconstitute systems that reproduce biological functions in vitro from individual elements in order to understand how the elements cooperate together to yield a function. Thirdly, we attempted to resolve biological structures at various resolutions ranging from the atomic to the cellular level to further our knowledge about the fundamental principles that various functions at the molecular level and to design artificial systems.

Download or read book Cardio Oncology written by Roberta A. Gottlieb and published by Academic Press. This book was released on 2016-11-26 with total page 358 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cardio-Oncology: Principles, Prevention and Management is a clinical volume that focuses on the basic science of cardio-oncology, addresses cardiotoxicity as a consequence of cancer therapy, and discusses prevention, diagnosis and management of cardiovascular disease in patients with cancer. This comprehensive volume presents unique perspectives ranging from basic science to clinical medicine in the field of cardio-oncology. It would be a valuable resource for cardiologists, oncologists, internists, and pediatricians caring for patients with cancer who have cardiovascular risk factors, as well as for cardio-oncology researchers. Covers basic science of cardio-oncology to provide readers with the necessary background Addresses cardiotoxicity related to current cancer therapeutic modalities Discusses diagnostic and management approaches of patients with underlying cardiac risk factors as well as otherwise healthy cancer patients

Download or read book Comprehensive Biophysics written by and published by Academic Press. This book was released on 2012-04-12 with total page 3533 pages. Available in PDF, EPUB and Kindle. Book excerpt: Biophysics is a rapidly-evolving interdisciplinary science that applies theories and methods of the physical sciences to questions of biology. Biophysics encompasses many disciplines, including physics, chemistry, mathematics, biology, biochemistry, medicine, pharmacology, physiology, and neuroscience, and it is essential that scientists working in these varied fields are able to understand each other's research. Comprehensive Biophysics, Nine Volume Set will help bridge that communication gap. Written by a team of researchers at the forefront of their respective fields, under the guidance of Chief Editor Edward Egelman, Comprehensive Biophysics, Nine Volume Set provides definitive introductions to a broad array of topics, uniting different areas of biophysics research - from the physical techniques for studying macromolecular structure to protein folding, muscle and molecular motors, cell biophysics, bioenergetics and more. The result is this comprehensive scientific resource - a valuable tool both for helping researchers come to grips quickly with material from related biophysics fields outside their areas of expertise, and for reinforcing their existing knowledge. Biophysical research today encompasses many areas of biology. These studies do not necessarily share a unique identifying factor. This work unites the different areas of research and allows users, regardless of their background, to navigate through the most essential concepts with ease, saving them time and vastly improving their understanding The field of biophysics counts several journals that are directly and indirectly concerned with the field. There is no reference work that encompasses the entire field and unites the different areas of research through deep foundational reviews. Comprehensive Biophysics fills this vacuum, being a definitive work on biophysics. It will help users apply context to the diverse journal literature offering, and aid them in identifying areas for further research Chief Editor Edward Egelman (E-I-C, Biophysical Journal) has assembled an impressive, world-class team of Volume Editors and Contributing Authors. Each chapter has been painstakingly reviewed and checked for consistent high quality. The result is an authoritative overview which ties the literature together and provides the user with a reliable background information and citation resource

Download or read book Muscle Physiology and Biochemistry written by Shoichi Imai and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 201 pages. Available in PDF, EPUB and Kindle. Book excerpt: The papers in this volume were contributed by close friends, co-workers and pupils of Professor Setsuro Ebashi. They are dedicated to him to commemorate his great and pioneering contribution to the advancement of muscle physiology and biochemistry, which, in time, exerted a great influence on the whole field of life science. We believe that this issue reveals the present state of research on muscle and/or calcium that was opened up by Professor Ebashi.