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Marius Sudol - One of the best experts on this subject based on the ideXlab platform.
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characterizing WW Domain interactions of tumor suppressor WWox reveals its association with multiprotein networks
Journal of Biological Chemistry, 2014Co-Authors: Mohammad Abuodeh, Marius Sudol, Zaidoun Salah, Tomer Barmag, Haiming Huang, Suhaib K Abdeen, Dana Reichmann, Sachdev S Sidhu, Rami I AqeilanAbstract:WW Domains are small modules present in regulatory and signaling proteins that mediate specific protein-protein interactions. The WW Domain-containing oxidoreductase (WWOX) encodes a 46-kDa tumor suppressor that contains two N-terminal WW Domains and a central short-chain dehydrogenase/reductase Domain. Based on its ligand recognition motifs, the WW Domain family is classified into four groups. The largest one, to which WWOX belongs, recognizes ligands with a PPXY motif. To pursue the functional properties of the WW Domains of WWOX, we employed mass spectrometry and phage display experiments to identify putative WWOX-interacting partners. Our analysis revealed that the first WW (WW1) Domain of WWOX is the main functional interacting Domain. Furthermore, our study uncovered well known and new PPXY-WW1-interacting partners and shed light on novel LPXY-WW1-interacting partners of WWOX. Many of these proteins are components of multiprotein complexes involved in molecular processes, including transcription, RNA processing, tight junction, and metabolism. By utilizing GST pull-down and immunoprecipitation assays, we validated that WWOX is a substrate of the E3 ubiquitin ligase ITCH, which contains two LPXY motifs. We found that ITCH mediates Lys-63-linked polyubiquitination of WWOX, leading to its nuclear localization and increased cell death. Our data suggest that the WW1 Domain of WWOX provides a versatile platform that links WWOX with individual proteins associated with physiologically important networks.
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Molecular insights into the WW Domain of the Golabi-Ito-Hall syndrome protein PQBP1.
FEBS Letters, 2012Co-Authors: Marius Sudol, Caleb B. Mcdonald, Amjad FarooqAbstract:The WW Domain-containing PQBP1 (polyglutamine tract-binding protein 1) protein regulates mRNA processing and gene transcription. Mutations in the PQBP1 gene were reported in several X chromosome-linked intellectual disability (XLID) disorders, including Golabi-Ito-Hall (GIH) syndrome. The missense mutation in the GIH syndrome maps within a functional region of the PQBP1 protein known as the WW Domain. The causative mutation of PQBP1 replaces the conserved tyrosine (Y) at position 65 within the aromatic core of the WW Domain to cysteine (C), which is a chemically significant change. In this short review, we analyze structural models of the Y65C mutated and wild type WW Domains of PQBP1 in order to infer potential molecular mechanisms that render the mutated PQBP1 protein inactive in terms of ligand binding and its function as a regulator of mRNA splicing.
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Protein Science Encyclopedia - The WW Domain
Protein Science Encyclopedia, 2008Co-Authors: Marius SudolAbstract:Originally published in: Modular Protein Domains. Edited by Giovanni Cesareni, Mario Gimona, Marius Sudol and Michael Yaffe. Copyright © 2005 Wiley-VCH Verlag GmbH & Co. KGaA Weinheim. Print ISBN: 3-527-30813-2 The sections in this article are Introduction and Brief History of Module Discovery Structure of the WW Domain-Ligand Complex WW Domains and Human Diseases From Liddle's Syndrome to Liddle's Disease Amyloid Precursor Protein: APP and FE65 Dystrophin WW Domain and Muscular Dystrophy Emerging Directions and Recent Developments AxCell's Map ErbB4 Receptor Protein-Tyrosine Kinase and its WW Domain-containing Adaptor, YAP Membrane Proteins with PPxYs Implicated in Cancer Conclusions Acknowledgements Keywords: modular protein Domains; WW Domain; structure of WW Domain-ligand complex; WW Domains and human diseases; recent developments
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WW Domain containing proteins WWox and yap compete for interaction with erbb 4 and modulate its transcriptional function
Cancer Research, 2005Co-Authors: Rami I Aqeilan, Marius Sudol, Valentina Donati, Alexey Palamarchuk, Francesco Trapasso, Mohamed Kaou, Yuri Pekarsky, Carlo M CroceAbstract:The WW Domain–containing oxidoreductase, WWOX , is a tumor suppressor that is deleted or altered in several cancer types. We recently showed that WWOX interacts with p73 and AP-2γ and suppresses their transcriptional activity. Yes-associated protein (YAP), also containing WW Domains, was shown to associate with p73 and enhance its transcriptional activity. In addition, YAP interacts with ErbB-4 receptor tyrosine kinase and acts as transcriptional coactivator of the COOH-terminal fragment (CTF) of ErbB-4. Stimulation of ErbB-4–expressing cells with 12- O -tetradecanoylphorbol-13-acetate (TPA) results in the proteolytic cleavage of its cytoplasmic Domain and translocation of this Domain to the nucleus. Here we report that WWOX physically associates with the full-length ErbB-4 via its first WW Domain. Coexpression of WWOX and ErbB-4 in HeLa cells followed by treatment with TPA results in the retention of ErbB-4 in the cytoplasm. Moreover, in MCF-7 breast carcinoma cells, expressing high levels of endogenous WWOX, endogenous ErbB-4 is also retained in the cytoplasm. In addition, our results show that interaction of WWOX and ErbB-4 suppresses transcriptional coactivation of CTF by YAP in a dose-dependent manner. A mutant form of WWOX lacking interaction with ErbB-4 has no effect on this coactivation of ErbB-4. Furthermore, WWOX is able to inhibit coactivation of p73 by YAP. In summary, our data indicate that WWOX antagonizes the function of YAP by competing for interaction with ErbB-4 and other targets and thus affect its transcriptional activity.
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WW Domain containing protein yap associates with erbb 4 and acts as a co transcriptional activator for the carboxyl terminal fragment of erbb 4 that translocates to the nucleus
Journal of Biological Chemistry, 2003Co-Authors: Akihiko Komuro, Makoto Nagai, Nicholas Navin, Marius SudolAbstract:Abstract The ErbB-4 receptor protein-tyrosine kinase is proteolytically processed by membrane proteases in response to the ligand or 12-O-tetradecanoylphorbol-13-acetate stimulation resulting in the cytoplasmic fragment translocating to the cell nucleus. The WW Domain-containing co-transcriptional activator Yes-associated protein (YAP) associates physically with the full-length ErbB-4 receptor and functionally with the ErbB-4 cytoplasmic fragment in the nucleus. The YAP·ErbB4 complex is mediated by the first WW Domain of YAP and the most carboxyl-terminal PPXY motif of ErbB-4. In human tissues, we documented the expression of YAP1 with a single WW Domain and YAP2 with two WW Domains. It is known that the COOH-terminal fragment of ErbB4 does not have transcriptional activity by itself; however, we show here that in the presence of YAP its transcriptional activity is revealed. There is a difference in the extent of transactivation activity among YAP isoforms: YAP2 is the stronger activator compared with YAP1. This transactivation is abolished by mutations that abrogate the YAP·ErbB4 complex formation. The unphosphorylatable mutation that increases the nuclear localization of YAP increases transcription activity. The COOH-terminal fragment of ErbB-4 and full-length YAP2 overexpressed in cells partially co-localize to the nucleus. Our data indicate that YAP is a potential signaling partner of the full-length ErbB4 receptor at the membrane and of the COOH-terminal fragment of ErbB-4 that translocates to the nucleus to regulate transcription.
Martin Gruebele - One of the best experts on this subject based on the ideXlab platform.
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parallel folding pathways of fip35 WW Domain explained by infrared spectra and their computer simulation
FEBS Letters, 2017Co-Authors: Laura Zanettipolzi, Martin Gruebele, Caitlin M Davis, Brian R Dyer, Andrea Amadei, Isabella DaidoneAbstract:We present a calculation of the amide I’ infrared spectra of the folded, unfolded, and intermediate states of the WW Domain Fip35, a model system for β-sheet folding. Using an all-atom molecular dy-namics simulation in which multiple folding and unfolding events take place we identify six conformational states and then apply perturbed matrix method quantum-mechanical calculations to determine their amide I’ infrared spectra. Our analysis focuses on two states pre-previously identified as Fip35 folding intermediates and suggests that a three-stranded core similar to the folded state core is the main source of the spectroscopic differences between the two intermediates. In particular, we propose a hypothesis for why folding via one of these intermediates was not experimentally observed by infrared T-jump. This article is protected by copyright. All rights reserved.
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high resolution mapping of the folding transition state of a WW Domain
Journal of Molecular Biology, 2016Co-Authors: Kapil Dave, Houbi Nguyen, Jeffery W. Kelly, Marcus Jäger, Martin GruebeleAbstract:Abstract Fast-folding WW Domains are among the best-characterized systems for comparing experiments and simulations of protein folding. Recent microsecond-resolution experiments and long duration (totaling milliseconds) single-trajectory modeling have shown that even mechanistic changes in folding kinetics due to mutation can now be analyzed. Thus, a comprehensive set of experimental data would be helpful to benchmark the predictions made by simulations. Here, we use T-jump relaxation in conjunction with protein engineering and report mutational Φ -values ( Φ M ) as indicators for folding transition-state structure of 65 side chain, 7 backbone hydrogen bond, and 6 deletion and /or insertion mutants within loop 1 of the 34-residue hPin1 WW Domain. Forty-five cross-validated consensus mutants could be identified that provide structural constraints for transition-state structure within all substructures of the WW Domain fold (hydrophobic core, loop 1, loop 2, β-sheet). We probe the robustness of the two hydrophobic clusters in the folding transition state, discuss how local backbone disorder in the native-state can lead to non-classical Φ M ‐values ( Φ M > 1) in the rate-determining loop 1 substructure, and conclusively identify mutations and positions along the sequence that perturb the folding mechanism from loop 1-limited toward loop 2-limited folding.
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ten microsecond molecular dynamics simulation of a fast folding WW Domain
Biophysical Journal, 2008Co-Authors: Peter L. Freddolino, Martin Gruebele, Klaus SchultenAbstract:All-atom molecular dynamics (MD) simulations of protein folding allow analysis of the folding process at an unprecedented level of detail. Unfortunately, such simulations have not yet reached their full potential both due to difficulties in sufficiently sampling the microsecond timescales needed for folding, and because the force field used may yield neither the correct dynamical sequence of events nor the folded structure. The ongoing study of protein folding through computational methods thus requires both improvements in the performance of molecular dynamics programs to make longer timescales accessible, and testing of force fields in the context of folding simulations. We report a ten-microsecond simulation of an incipient downhill-folding WW Domain mutant along with measurement of a molecular time and activated folding time of 1.5 microseconds and 13.3 microseconds, respectively. The protein simulated in explicit solvent exhibits several metastable states with incorrect topology and does not assume the native state during the present simulations.
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Ten-microsecond molecular dynamics simulation of a fast-folding WW Domain
Biophysical Journal, 2008Co-Authors: Peter L. Freddolino, Feng Liu, Martin Gruebele, Klaus SchultenAbstract:All-atom molecular dynamics (MD) simulations of protein folding allow analysis of the folding process at an unprecedented level of detail. Unfortunately, such simulations have not yet reached their full potential both due to difficulties in sufficiently sampling the microsecond timescales needed for folding, and because the force field used may yield neither the correct dynamical sequence of events nor the folded structure. The ongoing study of protein folding through computational methods thus requires both improvements in the performance of molecular dynamics programs to make longer timescales accessible, and testing of force fields in the context of folding simulations. We report a ten-microsecond simulation of an incipient downhill-folding WW Domain mutant along with measurement of a molecular time and activated folding time of 1.5 microseconds and 13.3 microseconds, respectively. The protein simulated in explicit solvent exhibits several metastable states with incorrect topology and does not assume the native state during the present simulations. © 2008 by the Biophysical Society.
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structure function folding relationship in a WW Domain
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Houbi Nguyen, Joseph P Noel, Marcus Jäger, Yan Zhang, Jan Bieschke, Maria T A Dendle, M E Bowman, Martin GruebeleAbstract:Protein folding barriers result from a combination of factors including unavoidable energetic frustration from nonnative interactions, natural variation and selection of the amino acid sequence for function, and/or selection pressure against aggregation. The rate-limiting step for human Pin1 WW Domain folding is the formation of the loop 1 substructure. The native conformation of this six-residue loop positions side chains that are important for mediating protein–protein interactions through the binding of Pro-rich sequences. Replacement of the wild-type loop 1 primary structure by shorter sequences with a high propensity to fold into a type-I′ β-turn conformation or the statistically preferred type-I G1 bulge conformation accelerates WW Domain folding by almost an order of magnitude and increases thermodynamic stability. However, loop engineering to optimize folding energetics has a significant downside: it effectively eliminates WW Domain function according to ligand-binding studies. The energetic contribution of loop 1 to ligand binding appears to have evolved at the expense of fast folding and additional protein stability. Thus, the two-state barrier exhibited by the wild-type human Pin1 WW Domain principally results from functional requirements, rather than from physical constraints inherent to even the most efficient loop formation process.
Jeffery W. Kelly - One of the best experts on this subject based on the ideXlab platform.
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high resolution mapping of the folding transition state of a WW Domain
Journal of Molecular Biology, 2016Co-Authors: Kapil Dave, Houbi Nguyen, Jeffery W. Kelly, Marcus Jäger, Martin GruebeleAbstract:Abstract Fast-folding WW Domains are among the best-characterized systems for comparing experiments and simulations of protein folding. Recent microsecond-resolution experiments and long duration (totaling milliseconds) single-trajectory modeling have shown that even mechanistic changes in folding kinetics due to mutation can now be analyzed. Thus, a comprehensive set of experimental data would be helpful to benchmark the predictions made by simulations. Here, we use T-jump relaxation in conjunction with protein engineering and report mutational Φ -values ( Φ M ) as indicators for folding transition-state structure of 65 side chain, 7 backbone hydrogen bond, and 6 deletion and /or insertion mutants within loop 1 of the 34-residue hPin1 WW Domain. Forty-five cross-validated consensus mutants could be identified that provide structural constraints for transition-state structure within all substructures of the WW Domain fold (hydrophobic core, loop 1, loop 2, β-sheet). We probe the robustness of the two hydrophobic clusters in the folding transition state, discuss how local backbone disorder in the native-state can lead to non-classical Φ M ‐values ( Φ M > 1) in the rate-determining loop 1 substructure, and conclusively identify mutations and positions along the sequence that perturb the folding mechanism from loop 1-limited toward loop 2-limited folding.
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sequence determinants of thermodynamic stability in a WW Domain an all β sheet protein
Protein Science, 2009Co-Authors: Marcus Jäger, Maria T A Dendle, Jeffery W. KellyAbstract:The stabilities of 66 sequence variants of the human Pin1 WW Domain have been determined by equilibrium thermal denaturation experiments. All 34 residues composing the hPin1 WW three-stranded β-sheet structure could be replaced one at a time with at least one different natural or non-natural amino acid residue without leading to an unfolded protein. Alanine substitutions at only four positions within the hPin1 WW Domain lead to a partially or completely unfolded protein—in the absence of a physiological ligand. The side chains of these four residues form a conserved, partially solvent-inaccessible, continuous hydrophobic minicore comprising the N- and C-termini. Ala mutations at five other residues, three of which constitute the ligand binding patch on the concave side of the β-sheet, significantly destabilize the hPin1 WW Domain without leading to an unfolded protein. The remaining mutations affect protein stability only slightly, suggesting that only a small subset of side chain interactions within the hPin1 WW Domain are mandatory for acquiring and maintaining a stable, cooperatively folded β-sheet structure.
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Sequence determinants of thermodynamic stability in a WW Domain—An all‐β‐sheet protein
Protein Science, 2009Co-Authors: Marcus Jäger, Maria T A Dendle, Jeffery W. KellyAbstract:The stabilities of 66 sequence variants of the human Pin1 WW Domain have been determined by equilibrium thermal denaturation experiments. All 34 residues composing the hPin1 WW three-stranded β-sheet structure could be replaced one at a time with at least one different natural or non-natural amino acid residue without leading to an unfolded protein. Alanine substitutions at only four positions within the hPin1 WW Domain lead to a partially or completely unfolded protein—in the absence of a physiological ligand. The side chains of these four residues form a conserved, partially solvent-inaccessible, continuous hydrophobic minicore comprising the N- and C-termini. Ala mutations at five other residues, three of which constitute the ligand binding patch on the concave side of the β-sheet, significantly destabilize the hPin1 WW Domain without leading to an unfolded protein. The remaining mutations affect protein stability only slightly, suggesting that only a small subset of side chain interactions within the hPin1 WW Domain are mandatory for acquiring and maintaining a stable, cooperatively folded β-sheet structure.
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tuning the free energy landscape of a WW Domain by temperature mutation and truncation
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Houbi Nguyen, Martin Gruebele, Marcus Jäger, Alessandro Moretto, Jeffery W. KellyAbstract:Abstract The equilibrium unfolding of the Formin binding protein 28 (FBP) WW Domain, a stable three-stranded β-sheet protein, can be described as reversible apparent two-state folding. Kinetics studied by laser temperature jump reveal a third state at temperatures below the midpoint of unfolding. The FBP free-energy surface can be tuned between three-state and two-state kinetics by changing the temperature, by truncation of the C terminus, or by selected point mutations. FBP WW Domain is the smallest three-state folder studied to date and the only one that can be freely tuned between three-state and apparent two-state folding by several methods (temperature, truncation, and mutation). Its small size (28–37 residues), the availability of a quantitative reaction coordinate (φT), the fast folding time scale (10s of μs), and the tunability of the folding routes by small temperature or sequence changes make this system the ideal prototype for studying more subtle features of the folding free-energy landscape by simulations or analytical theory.
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the folding mechanism of a β sheet the WW Domain
Journal of Molecular Biology, 2001Co-Authors: Marcus Jäger, Houbi Nguyen, Jason C Crane, Jeffery W. Kelly, Martin GruebeleAbstract:The folding thermodynamics and kinetics of the Pin WW Domain, a three-stranded antiparallel β-sheet, have been characterized extensively. Folding and activation free energies were determined as a function of temperature for 16 mutants, which sample all strands and turns of the molecule. The mutational phi value (Φm) diagram is a smooth function of sequence, indicating a prevalence of local interactions in the transition state (TS). At 37 °C, the diagram has a single pronounced maximum at turn 1: the rate-limiting step during folding is the formation of loop 1. In contrast, key residues for thermodynamic stability are located in the strand hydrophobic clusters, indicating that factors contributing to protein stability and folding kinetics are not correlated. The location of the TS along the entropic reaction coordinate ΦT, obtained by temperature-tuning the kinetics, reveals that sufficiently destabilizing mutants in loop 2 or in the Leu7-Trp11-Tyr24-Pro37 hydrophobic cluster can cause a switch to a late TS. Φm analysis is usually applied “perturbatively” (methyl truncation), but with ΦT to quantitatively assess TS shifts along a reaction coordinate, more severe mutations can be used to probe regions of the free energy surface beyond the TS.
Marcus Jäger - One of the best experts on this subject based on the ideXlab platform.
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high resolution mapping of the folding transition state of a WW Domain
Journal of Molecular Biology, 2016Co-Authors: Kapil Dave, Houbi Nguyen, Jeffery W. Kelly, Marcus Jäger, Martin GruebeleAbstract:Abstract Fast-folding WW Domains are among the best-characterized systems for comparing experiments and simulations of protein folding. Recent microsecond-resolution experiments and long duration (totaling milliseconds) single-trajectory modeling have shown that even mechanistic changes in folding kinetics due to mutation can now be analyzed. Thus, a comprehensive set of experimental data would be helpful to benchmark the predictions made by simulations. Here, we use T-jump relaxation in conjunction with protein engineering and report mutational Φ -values ( Φ M ) as indicators for folding transition-state structure of 65 side chain, 7 backbone hydrogen bond, and 6 deletion and /or insertion mutants within loop 1 of the 34-residue hPin1 WW Domain. Forty-five cross-validated consensus mutants could be identified that provide structural constraints for transition-state structure within all substructures of the WW Domain fold (hydrophobic core, loop 1, loop 2, β-sheet). We probe the robustness of the two hydrophobic clusters in the folding transition state, discuss how local backbone disorder in the native-state can lead to non-classical Φ M ‐values ( Φ M > 1) in the rate-determining loop 1 substructure, and conclusively identify mutations and positions along the sequence that perturb the folding mechanism from loop 1-limited toward loop 2-limited folding.
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sequence determinants of thermodynamic stability in a WW Domain an all β sheet protein
Protein Science, 2009Co-Authors: Marcus Jäger, Maria T A Dendle, Jeffery W. KellyAbstract:The stabilities of 66 sequence variants of the human Pin1 WW Domain have been determined by equilibrium thermal denaturation experiments. All 34 residues composing the hPin1 WW three-stranded β-sheet structure could be replaced one at a time with at least one different natural or non-natural amino acid residue without leading to an unfolded protein. Alanine substitutions at only four positions within the hPin1 WW Domain lead to a partially or completely unfolded protein—in the absence of a physiological ligand. The side chains of these four residues form a conserved, partially solvent-inaccessible, continuous hydrophobic minicore comprising the N- and C-termini. Ala mutations at five other residues, three of which constitute the ligand binding patch on the concave side of the β-sheet, significantly destabilize the hPin1 WW Domain without leading to an unfolded protein. The remaining mutations affect protein stability only slightly, suggesting that only a small subset of side chain interactions within the hPin1 WW Domain are mandatory for acquiring and maintaining a stable, cooperatively folded β-sheet structure.
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Sequence determinants of thermodynamic stability in a WW Domain—An all‐β‐sheet protein
Protein Science, 2009Co-Authors: Marcus Jäger, Maria T A Dendle, Jeffery W. KellyAbstract:The stabilities of 66 sequence variants of the human Pin1 WW Domain have been determined by equilibrium thermal denaturation experiments. All 34 residues composing the hPin1 WW three-stranded β-sheet structure could be replaced one at a time with at least one different natural or non-natural amino acid residue without leading to an unfolded protein. Alanine substitutions at only four positions within the hPin1 WW Domain lead to a partially or completely unfolded protein—in the absence of a physiological ligand. The side chains of these four residues form a conserved, partially solvent-inaccessible, continuous hydrophobic minicore comprising the N- and C-termini. Ala mutations at five other residues, three of which constitute the ligand binding patch on the concave side of the β-sheet, significantly destabilize the hPin1 WW Domain without leading to an unfolded protein. The remaining mutations affect protein stability only slightly, suggesting that only a small subset of side chain interactions within the hPin1 WW Domain are mandatory for acquiring and maintaining a stable, cooperatively folded β-sheet structure.
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structure function folding relationship in a WW Domain
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Houbi Nguyen, Joseph P Noel, Marcus Jäger, Yan Zhang, Jan Bieschke, Maria T A Dendle, M E Bowman, Martin GruebeleAbstract:Protein folding barriers result from a combination of factors including unavoidable energetic frustration from nonnative interactions, natural variation and selection of the amino acid sequence for function, and/or selection pressure against aggregation. The rate-limiting step for human Pin1 WW Domain folding is the formation of the loop 1 substructure. The native conformation of this six-residue loop positions side chains that are important for mediating protein–protein interactions through the binding of Pro-rich sequences. Replacement of the wild-type loop 1 primary structure by shorter sequences with a high propensity to fold into a type-I′ β-turn conformation or the statistically preferred type-I G1 bulge conformation accelerates WW Domain folding by almost an order of magnitude and increases thermodynamic stability. However, loop engineering to optimize folding energetics has a significant downside: it effectively eliminates WW Domain function according to ligand-binding studies. The energetic contribution of loop 1 to ligand binding appears to have evolved at the expense of fast folding and additional protein stability. Thus, the two-state barrier exhibited by the wild-type human Pin1 WW Domain principally results from functional requirements, rather than from physical constraints inherent to even the most efficient loop formation process.
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tuning the free energy landscape of a WW Domain by temperature mutation and truncation
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Houbi Nguyen, Martin Gruebele, Marcus Jäger, Alessandro Moretto, Jeffery W. KellyAbstract:Abstract The equilibrium unfolding of the Formin binding protein 28 (FBP) WW Domain, a stable three-stranded β-sheet protein, can be described as reversible apparent two-state folding. Kinetics studied by laser temperature jump reveal a third state at temperatures below the midpoint of unfolding. The FBP free-energy surface can be tuned between three-state and two-state kinetics by changing the temperature, by truncation of the C terminus, or by selected point mutations. FBP WW Domain is the smallest three-state folder studied to date and the only one that can be freely tuned between three-state and apparent two-state folding by several methods (temperature, truncation, and mutation). Its small size (28–37 residues), the availability of a quantitative reaction coordinate (φT), the fast folding time scale (10s of μs), and the tunability of the folding routes by small temperature or sequence changes make this system the ideal prototype for studying more subtle features of the folding free-energy landscape by simulations or analytical theory.
Nanshan Chang - One of the best experts on this subject based on the ideXlab platform.
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WW Domain containing proteins yap and taz in the hippo pathway as key regulators in stemness maintenance tissue homeostasis and tumorigenesis
Frontiers in Oncology, 2019Co-Authors: Yuan Chen, Nanshan Chang, Chen Yu Lu, Tian You Cheng, Hsinfu ChenAbstract:The Hippo pathway is a conserved signaling pathway originally defined in Drosophila melanogaster two decades ago. Deregulation of the Hippo pathway leads to significant overgrowth in phenotypes and ultimately initiation of tumorigenesis in various tissues. The major WW Domain proteins in the Hippo pathway are YAP and TAZ, which regulate embryonic development, organ growth, tissue regeneration, stem cell pluripotency, and tumorigenesis. Recent reports reveal the novel roles of YAP/TAZ in establishing the precise balance of stem cell niches, promoting the production of induced pluripotent stem cells (iPSCs), and provoking signals for regeneration and cancer initiation. Activation of YAP, for example, results in expansion of progenitor cells, which promotes regeneration after tissue damage. YAP is highly expressed in self-renewing pluripotent stem cells. Overexpression of YAP halts stem cell differentiation and yet maintains the inherent stem cell properties. A success in reprograming iPSCs by the transfection of cells with Oct3/4, Sox2 and Yap expression constructs has recently been shown. In this review, we update the current knowledge and the latest progress in the WW Domain proteins of the Hippo pathway in relevance to stem cell biology, and provide a thorough understanding in the tissue homeostasis and identification of potential targets to block tumor development.
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strategies of oncogenic microbes to deal with WW Domain containing oxidoreductase
Experimental Biology and Medicine, 2015Co-Authors: Jenn Ren Hsiao, Yao Chang, Nanshan ChangAbstract:WW Domain-containing oxidoreductase (WWOX) is a well-documented tumor suppressor protein that controls growth, survival, and metastasis of malignant cells. To counteract WWOX’s suppressive effects, cancer cells have developed many strategies either to downregulate WWOX expression or to functionally inactivate WWOX. Relatively unknown is, in the context of those cancers associated with certain viruses or bacteria, how the oncogenic pathogens deal with WWOX. Here we review recent studies showing different strategies utilized by three cancer-associated pathogens. Helicobactor pylori reduces WWOX expression through promoter hypermethylation, an epigenetic mechanism also occurring in many other cancer cells. WWOX has a potential to block canonical NF-kB activation and tumorigenesis induced by Tax, an oncoprotein of human T-cell leukemia virus. Tax successfully overcomes the blockage by inhibiting WWOX expression through activation of the non-canonical NF-kB pathway. On the other hand, latent membrane protein 2A of Epstein–Barr virus physically interacts with WWOX and redirects its function to trigger a signaling pathway that upregulates matrix metalloproteinase 9 and cancer cell invasion. These reports may be just ‘‘the tip of the iceberg’’ regarding multiple interactions between WWOX and oncogenic microbes. Further studies in this direction should expand our understanding of infection-driven oncogenesis.
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signaling from membrane receptors to tumor suppressor WW Domain containing oxidoreductase
Experimental Biology and Medicine, 2010Co-Authors: Jean Yun Chang, Ruei Yu He, Qunying Hong, Sheanjen Chen, Nanshan ChangAbstract:The family of WW Domain-containing proteins contains over 2000 members. The small WW Domain module is responsible, in part, for protein/protein binding interactions and signaling. Many of these proteins are located at the membrane/cytoskeleton area, where they act as adaptors to receive signals from the cell surface. In this review, we provide molecular insights regarding recent novel findings on signaling from the cell surface toward WW Domain-containing oxidoreductase, known as WWOX, FOR or WOX1. More specifically, transforming growth factor beta 1 utilizes cell surface hyaluronidase Hyal-2 (hyaluronoglucosaminidase 2) as a cognate receptor for signaling with WWOX and Smad4 to control gene transcription, growth and death. Complement C1q alone, bypassing the activation of classical pathway, signals a novel event of apoptosis by inducing microvillus formation and WWOX activation. Deficiency in these signaling events appears to favorably support cancer growth.
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WW Domain containing oxidoreductase a candidate tumor suppressor
Trends in Molecular Medicine, 2007Co-Authors: Nanshan Chang, Hammming SheuAbstract:Common fragile site gene WWOX encodes a candidate tumor suppressor WW Domain-containing oxidoreductase. Alteration of this gene, along with dramatic downregulation of WWOX protein, is shown in the majority of invasive cancer cells. Ectopic WWOX exhibits proapoptotic and tumor inhibitory functions in vitro and in vivo, probably interacting with growth regulatory proteins p53, p73 and others. Hyaluronidases regulate WWOX expression, increase cancer invasiveness and seem to be involved in the development of hormone-independent growth of invasive cancer cells. Estrogen and androgen stimulate phosphorylation and nuclear translocation of WWOX, although binding of WWOX to these sex hormones is unknown. We propose that suppression of WWOX expression by overexpressed hyaluronidases might contribute in part to the development of hormone independence in invasive cancer.
