Investigating the Binding of Peptidyl-prolyl Isomerase Pin1 to a Multi-site Phosphorylated Substrate Modeled After Phosphatase CDC25C. PDF Download
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Author: Michelle K. Dubinsky
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
Pin1 is a human protein classified as a peptidyl-prolyl cis/trans isomerase. The protein regulates the conformation of phosphorylated protein substrates by rotating the peptide bond between phosphorylated serine/threonine residues that precede proline residues. Structurally, Pin1 consists of an N-terminal WW domain and a C-terminal PPIase domain. The PPIase domain catalyzes cis/trans isomerization of peptide bonds in substrate proteins that contain the aforementioned consensus motif. We hypothesize that Pin1 binding is positively impacted when two phospho-acceptor sites on peptides derived from mitotic phosphatase CDC25C, a known Pin1-interacting protein, are phosphorylated. Using nuclear magnetic resonance and fluorescence polarization, binding affinities of CDC25C peptides to Pin1 were calculated. The results indicate that doubly-phosphorylated peptides bound to Pin1 have lower dissociation constants and consequently greater binding affinities, than complexes containing non- or singly-phosphorylated peptides, at the equivalent residues. This suggests that Pin1 has two independent phospho-binding sites that when bound, increase substrate binding affinity.
Author: Michelle K. Dubinsky
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
Pin1 is a human protein classified as a peptidyl-prolyl cis/trans isomerase. The protein regulates the conformation of phosphorylated protein substrates by rotating the peptide bond between phosphorylated serine/threonine residues that precede proline residues. Structurally, Pin1 consists of an N-terminal WW domain and a C-terminal PPIase domain. The PPIase domain catalyzes cis/trans isomerization of peptide bonds in substrate proteins that contain the aforementioned consensus motif. We hypothesize that Pin1 binding is positively impacted when two phospho-acceptor sites on peptides derived from mitotic phosphatase CDC25C, a known Pin1-interacting protein, are phosphorylated. Using nuclear magnetic resonance and fluorescence polarization, binding affinities of CDC25C peptides to Pin1 were calculated. The results indicate that doubly-phosphorylated peptides bound to Pin1 have lower dissociation constants and consequently greater binding affinities, than complexes containing non- or singly-phosphorylated peptides, at the equivalent residues. This suggests that Pin1 has two independent phospho-binding sites that when bound, increase substrate binding affinity.
Author: Dana Onica
Publisher:
ISBN:
Category :
Languages : en
Pages : 228
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Book Description
The enzyme Pin1 is a peptidyl-prolyl cis-trans isomerase consisting structurally of two domains, an N-terminal WW protein interaction domain and a C-terminal PPIase catalytic domain. Both domains bind a phosphorylated serine/threonine-proline motif, however, a precise mechanism regarding how binding to interactors is coordinated by both domains has not yet been determined. Although multiple models exist to explain this process, it appears that the interactions may be substrate-specific. With regards to a well-studied Pin1 interactor, CDC25C, we hypothesize that binding occurs via the simultaneous model. This model suggests that two binding sites, each having low affinity, may bind in concert producing a higher affinity interaction. To investigate this we chose to employ a peptide-based approach, using human CDC25C-derived peptides which contained the two identified Pin1 binding sites in phosphorylated and non-phosphorylated combinations. These peptides were utilized in two independent assays, surface plasmon resonance and fluorescence polarization, to elucidate the domain- and phosphorylation-requirements of the Pin1-CDC 25C interaction. We showed that the interaction is phosphorylation-dependent, and is optimal when full- length, wild-type Pin1 binds to a doubly-phosphorylated peptide. Collectively, our results support our hypothesis that the Pin1-CDC25C interaction occurs via the simultaneous model, and requires both domains.
Author: Hewa Pathiranalage Dinusha S. Jinasena
Publisher:
ISBN:
Category :
Languages : en
Pages : 126
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Book Description
Pin1 is an essential peptidyl-prolyl isomerase (PPIase) that catalyzes cis-trans prolyl isomerization in proteins containing phosphorylated serine/threonine-proline motifs (pSer/Thr-Pro). It has an N-terminal binding domain (WW) and a C-terminal PPIase domain. Pin1 targets pSer/Thr-Pro motifs by its WW domain and catalyzes isomerization through its PPIase domain. This dissertation is focused on elucidating the interactions between Pin1/substrate, the inter-domain dynamics upon binding, and the catalytic activity of Pin1 upon binding different substrates. Specifically, we investigated the Pin1-Histone H1 interaction and designed a series of chimeric peptides based on the H1.4 sequence (KATGAApTPKKSAKW). NMR titrations were performed for each peptide using both full-length Pin1 as well as the WW domain alone, to analyze the binding affinities. Here we combined 15N relaxation and residual dipolar couplings (RDCs) to monitor the degree to which peptide binding induced inter-domain interactions. We also investigated whether our chimeric sequences could alter catalysis (kex) using 1H-1H EXSY NMR experiments. Finally, when combined with molecular modeling, our results suggest a structural basis for how substrate binding can alter Pin1 inter-domain dynamics..
Author: Cai Huang
Publisher: BoD – Books on Demand
ISBN: 9535107372
Category : Medical
Languages : en
Pages : 482
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Book Description
15 chapters on protein phosphorylation and human health written by expert scientists. Covers most important research hot points, such as Akt, AMPK and mTOR. Bridges the basic protein phosphorylation pathways with human health and diseases. Detailed and comprehensive text with excellent figure illustration.
Author: Nancy Y. Ip
Publisher: Springer Science & Business Media
ISBN: 0387788875
Category : Medical
Languages : en
Pages : 326
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Book Description
Cyclin Dependent Kinase 5 provides a comprehensive and up-to-date collection of reviews on the discovery, signaling mechanisms and functions of Cdk5, as well as the potential implication of Cdk5 in the treatment of neurodegenerative diseases. Since the identification of this unique member of the Cdk family, Cdk5 has emerged as one of the most important signal transduction mediators in the development, maintenance and fine-tuning of neuronal functions and networking. Further studies have revealed that Cdk5 is also associated with the regulation of neuronal survival during both developmental stages and in neurodegenerative diseases. These observations indicate that precise control of Cdk5 is essential for the regulation of neuronal survival. The pivotal role Cdk5 appears to play in both the regulation of neuronal survival and synaptic functions thus raises the interesting possibility that Cdk5 inhibitors may serve as therapeutic treatment for a number of neurodegenerative diseases.
Author: Marc Thiriet
Publisher: Springer Science & Business Media
ISBN: 1461443695
Category : Science
Languages : en
Pages : 1073
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Book Description
The volumes in this authoritative series present a multidisciplinary approach to modeling and simulation of flows in the cardiovascular and ventilatory systems, especially multiscale modeling and coupled simulations. The cardiovascular and respiratory systems are tightly coupled, as their primary function is to supply oxygen to and remove carbon dioxide from the body's cells. Because physiological conduits have deformable and reactive walls, macroscopic flow behavior and prediction must be coupled to phenomenological models of nano- and microscopic events in a corrector scheme of regulated mechanisms when the vessel lumen caliber varies markedly. Therefore, investigation of flows of blood and air in physiological conduits requires an understanding of the biology, chemistry, and physics of these systems together with the mathematical tools to describe their functioning. Volume 4 is devoted to major sets of intracellular mediators that transmit signals upon stimulation of cell-surface receptors. Activation of signaling effectors triggers the release of substances stored in cellular organelles and/or gene transcription and protein synthesis. Complex stages of cell signaling can be studied using proper mathematical models, once the role of each component is carefully handled. Volume 4 also reviews various categories of cytosolic and/or nuclear mediators and illustrates some major signal transduction pathways, such as NFkappaB axis, oxygen sensing, and mechanotransduction.
Author: Sivapatham Sundaresan
Publisher:
ISBN: 9781838805357
Category : Cancer
Languages : en
Pages :
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Author: Jiayang Li
Publisher: Academic Press
ISBN: 0128115637
Category : Science
Languages : en
Pages : 618
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Book Description
Plant Hormones: Biosynthesis and Mechanisms of Action is based on research funded by the Chinese government’s National Natural Science Foundation of China (NSFC). This book brings a fresh understanding of hormone biology, particularly molecular mechanisms driving plant hormone actions. With growing understanding of hormone biology comes new outlooks on how mankind values and utilizes the built-in potential of plants for improvement of crops in an environmentally friendly and sustainable manner. This book is a comprehensive description of all major plant hormones: how they are synthesized and catabolized; how they are perceived by plant cells; how they trigger signal transduction; how they regulate gene expression; how they regulate plant growth, development and defense responses; and how we measure plant hormones. This is an exciting time for researchers interested in plant hormones. Plants rely on a diverse set of small molecule hormones to regulate every aspect of their biological processes including development, growth, and adaptation. Since the discovery of the first plant hormone auxin, hormones have always been the frontiers of plant biology. Although the physiological functions of most plant hormones have been studied for decades, the last 15 to 20 years have seen a dramatic progress in our understanding of the molecular mechanisms of hormone actions. The publication of the whole genome sequences of the model systems of Arabidopsis and rice, together with the advent of multidisciplinary approaches has opened the door to successful experimentation on plant hormone actions. Offers a comprehensive description of all major plant hormones including the recently discovered strigolactones and several peptide hormones Contains a chapter describing how plant hormones regulate stem cells Offers a fresh understanding of hormone biology, particularly molecular mechanisms driving plant hormone actions Discusses the built-in potential of plants for improvement of crops in an environmentally friendly and sustainable manner
Author: Terri L. Tanielian
Publisher: Rand Corporation
ISBN: 0833044540
Category : Business & Economics
Languages : en
Pages : 499
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Book Description
Since October 2001, approximately 1.64 million U.S. troops have been deployed for Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) in Afghanistan and Iraq. Early evidence suggests that the psychological toll of these deployments -- many involving prolonged exposure to combat-related stress over multiple rotations -- may be disproportionately high compared with the physical injuries of combat. In the face of mounting public concern over post-deployment health care issues confronting OEF/OIF veterans, several task forces, independent review groups, and a Presidential Commission have been convened to examine the care of the war wounded and make recommendations. Concerns have been most recently centered on two combat-related injuries in particular: post-traumatic stress disorder and traumatic brain injury. With the increasing incidence of suicide and suicide attempts among returning veterans, concern about depression is also on the rise. The study discussed in this monograph focuses on post-traumatic stress disorder, major depression, and traumatic brain injury, not only because of current high-level policy interest but also because, unlike the physical wounds of war, these conditions are often invisible to the eye, remaining invisible to other servicemembers, family members, and society in general. All three conditions affect mood, thoughts, and behavior; yet these wounds often go unrecognized and unacknowledged. The effect of traumatic brain injury is still poorly understood, leaving a large gap in knowledge related to how extensive the problem is or how to address it. RAND conducted a comprehensive study of the post-deployment health-related needs associated with these three conditions among OEF/OIF veterans, the health care system in place to meet those needs, gaps in the care system, and the costs associated with these conditions and with providing quality health care to all those in need. This monograph presents the results of our study, which should be of interest to mental health treatment providers; health policymakers, particularly those charged with caring for our nation's veterans; and U.S. service men and women, their families, and the concerned public. All the research products from this study are available at http://veterans.rand.org. Data collection for this study began in April 2007and concluded in January 2008. Specific activities included a critical reviewof the extant literature on the prevalence of post-traumatic stress disorder, major depression, and traumatic brain injury and their short- and long-term consequences; a population-based survey of service members and veterans who served in Afghanistan or Iraq to assess health status and symptoms, as well asutilization of and barriers to care; a review of existing programs to treat service members and veterans with the three conditions; focus groups withmilitary service members and their spouses; and the development of a microsimulation model to forecast the economic costs of these conditions overtime. Among our recommendations is that effective treatments documented in the scientific literature -- evidence-based care -- are available for PTSD and major depression. Delivery of such care to all veterans with PTSD or majordepression would pay for itself within two years, or even save money, by improving productivity and reducing medical and mortality costs. Such care may also be a cost-effective way to retain a ready and healthy military force for the future. However, to ensure that this care is delivered requires system-level changes across the Department of Defense, the Department of Veterans Affairs, and the U.S. health care system.
Author: Isabella Dalle-Donne
Publisher: John Wiley & Sons
ISBN: 0471973114
Category : Science
Languages : en
Pages : 978
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Book Description
Methodology and applications of redox proteomics The relatively new and rapidly changing field of redox proteomics has the potential to revolutionize how we diagnose disease, assess risks, determine prognoses, and target therapeutic strategies for people with inflammatory and aging-associated diseases. This collection brings together, in one comprehensive volume, a broad array of information and insights into normal and altered physiology, molecular mechanisms of disease states, and new applications of the rapidly evolving techniques of proteomics. Written by some of the finest investigators in this area, Redox Proteomics: From Protein Modifications to Cellular Dysfunction and Diseases examines the key topics of redox proteomics and redox control of cellular function, including: * The role of oxidized proteins in various disorders * Pioneering studies on the development of redox proteomics * Analytical methodologies for identification and structural characterization of proteins affected by oxidative/nitrosative modifications * The response and regulation of protein oxidation in different cell types * The pathological implications of protein oxidation for conditions, including asthma, cardiovascular disease, diabetes, preeclampsia, and Alzheimer's disease Distinguished by its in-depth discussions, balanced methodological approach, and emphasis on medical applications and diagnosis development, Redox Proteomics is a rich resource for all professionals with an interest in proteomics, cellular physiology and its alterations in disease states, and related fields.
