Phosphorylation-Dependent Peptidyl-Prolyl Cis/Trans Isomerase PIN1 PDF Download
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Author: Jormay Lim
Publisher: Frontiers Media SA
ISBN: 2889663817
Category : Science
Languages : en
Pages : 140
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Book Description
Author: Jormay Lim
Publisher: Frontiers Media SA
ISBN: 2889663817
Category : Science
Languages : en
Pages : 140
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Book Description
Author: Colleen D. Behrsin
Publisher:
ISBN:
Category :
Languages : en
Pages : 356
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Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 460
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Estrogen receptor-alpha (ER[alpha]) is a member of nuclear receptor superfamily of transcription factors. It is known to regulate carcinogenic gene expression programs that are involved in the development and progression of breast cancer. The transcriptional function of ER[alpha] is mediated by a C-terminal AF2 and an N-terminal AF1 activation domains. Ligand-dependent AF2 activity is well-characterized and serves as a basis for hormonal therapy for breast cancer. In contrast, structural and functional mechanisms governing AF1 functions remain poorly understood. AF1 activity of ER[alpha] is regulated by phosphorylation stemming from hormone, peptide growth factors, and second messenger pathways. Paradoxically, phosphorylation results in contrasting responses (differentiation and growth, protein stability and degradation, agonist and antagonist activities). How phosphorylation translates into diverse outcome is not clearly understood. The work presented in this thesis has uncovered a post-translation modification beyond phosphorylation that regulates the function and fate of ER[alpha]. I found that phosphorylation-dependent prolyl cis/trans isomerase, Pin1, causes structural changes at the AF1 region of ER[alpha]. These local changes allosterically regulate DNA binding and dimerization activities, enhancing overall ER[alpha] transcriptional function. Pin1 also stabilizes ER[alpha] protein by blocking its ubiquitination and degradation by the proteasome. Further studies in understanding the role of Pin1 in breast cancer led us to uncover the importance of Pin1 in proliferation of ER[alpha]-positive breast cancer cells and mammary tumors in rodent models. Pin1 overexpression was sufficient to overcome the antagonistic effects of tamoxifen and also contributed to tamoxifen resistance in breast cancer cells. Finally, the clinical relevance of Pin1 activity was confirmed by our findings in human breast tumors, where Pin1 levels were correlated with ER[alpha] protein levels, and ER[alpha]-positive tumor patients with high Pin1 levels had poor overall survival. Overall, the findings in this thesis have identified a new regulatory mechanism governing ER[alpha] AF1 function in breast cancer and discovered Pin1 as an important component modulating ER[alpha] protein levels and transactivation functions.
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: 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: Atta-ur-Rahman
Publisher: Bentham Science Publishers
ISBN: 1608058085
Category : Medical
Languages : en
Pages : 388
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Book Description
Frontiers in Anti-Cancer Drug Discovery is an Ebook series devoted to publishing the latest and the most important advances in Anti-Cancer drug design and discovery. Eminent scientists write contributions on all areas of rational drug design and drug discovery including medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, recent important patents, and structure-activity relationships. The Ebook series should prove to be of interest to all pharmaceutical scientists involved in research in Anti-Cancer drug design and discovery. Each volume is devoted to the major advances in Anti-Cancer drug design and discovery. The Ebook series is essential reading to all scientists involved in drug design and discovery who wish to keep abreast of rapid and important developments in the field.
Author: Thomas E. Creighton
Publisher: Macmillan
ISBN: 9780716770305
Category : Medical
Languages : en
Pages : 534
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Book Description
Organized on a combined basis of chronology and of structural and functional hierarchy, This comprehensive text describes all aspects of proteins--biosynthesis, evolution, dynamics, ligand binding, catalysis, and energy transduction--not just their structures. This edition (first was 1984) is thoroughly updated--especially in the area of protein biosynthesis--and features end-of-chapter exercises and problems, many of which require the student to consult the cited literature in order to obtain the answer. Annotation copyright by Book News, Inc., Portland, OR
Author: Sivapatham Sundaresan
Publisher:
ISBN: 9781838805357
Category : Cancer
Languages : en
Pages :
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Author:
Publisher: ScholarlyEditions
ISBN: 1464921814
Category : Medical
Languages : en
Pages : 410
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Book Description
Enzymes: Advances in Research and Application: 2011 Edition is a ScholarlyEditions™ eBook that delivers timely, authoritative, and comprehensive information about Enzymes and Coenzymes. The editors have built Enzymes: Advances in Research and Application: 2011 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Enzymes and Coenzymes in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Enzymes: Advances in Research and Application: 2011 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
Author: Andrea Barberis
Publisher: Frontiers Media SA
ISBN: 2889197328
Category : Learning
Languages : en
Pages : 177
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Book Description
Learning and memory are believed to depend on plastic changes of neuronal circuits due to activity-dependent potentiation or depression of specific synapses. During the last two decades, plasticity of brain circuits was hypothesized to mainly rely on the flexibility of glutamatergic excitatory synapses, whereas inhibitory synapses were assumed relatively invariant, to ensure stable and reliable control of the neuronal network. As a consequence, while considerable efforts were made to clarify the main mechanisms underlying plasticity at excitatory synapses, the study of the cellular/molecular mechanisms of inhibitory plasticity has received much less attention. Nevertheless, an increasing body of evidence has revealed that inhibitory synapses undergo several types of plasticity at both pre- and postsynaptic levels. Given the crucial role of inhibitory interneurons in shaping network activities, such as generation of oscillations, selection of cell assemblies and signal integration, modifications of the inhibitory synaptic strength represents an extraordinary source of versatility for the fine control of brain states. This versatility also results from the rich diversity of GABAergic neurons in several brain areas, the specific role played by each inhibitory neuron subtype within a given circuit, and the heterogeneity of the properties and modulation of GABAergic synapses formed by specific interneuron classes. The molecular mechanisms underlying the potentiation or depression of inhibitory synapses are now beginning to be unraveled. At the presynaptic level, retrograde synaptic signaling was demonstrated to modulate GABA release, whereas postsynaptic forms of plasticity involve changes in the number/gating properties of GABAA receptors and/or shifts of chloride gradients. In addition, recent research indicates that GABAergic tonic inhibition can also be plastic, adding a further level of complexity to the control of the excitatory/inhibitory balance in the brain. The present Topic will focus on plasticity of GABAergic synapses, with special emphasis on the molecular mechanisms of plasticity induction and/or expression.
