scholarly journals Quantitative mapping of protein-peptide affinity landscapes using spectrally encoded beads

2018 ◽  
Author(s):  
Huy Nguyen ◽  
Jagoree Roy ◽  
Björn Harink ◽  
Nikhil Damle ◽  
Brian Baxter ◽  
...  
Keyword(s):  
Computational Modeling ◽  
Protein Phosphatase ◽  
Therapeutic Potential ◽  
Signaling Networks ◽  
Post Translational Modifications ◽  
Inhibitory Peptides ◽  
Quantitative Measurements ◽  
Quantitative Mapping ◽  
Linear Motifs ◽  
Peptide Affinity

AbstractTransient, regulated binding of globular protein domains to Short Linear Motifs (SLiMs) in disordered regions of other proteins drives cellular signaling. Mapping the energy landscapes of these interactions is essential for deciphering and therapeutically perturbing signaling networks, but is challenging due to their weak affinities. We present a powerful technology, MRBLE-pep, that simultaneously quantifies protein binding to a library of peptides directly synthesized on beads containing unique spectral codes. Using computational modeling and MRBLE-pep, we systematically probe binding of calcineurin (CN), a conserved protein phosphatase essential for the immune response and target of immunosuppressants, to the PxIxIT SLiM. We establish that flanking residues and post- translational modifications critically contribute to PxIxIT-CN affinity, and discover CN-inhibitory peptides with unprecedented affinity and therapeutic potential. The quantitative measurements provided by this approach will improve computational modeling efforts, elucidate a broad range of weak protein-SLiM interactions, and revolutionize our understanding of signaling networks.

scholarly journals Quantitative mapping of protein-peptide affinity landscapes using spectrally encoded beads

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Huy Quoc Nguyen ◽  
Jagoree Roy ◽  
Björn Harink ◽  
Nikhil P Damle ◽  
Naomi R Latorraca ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Signaling Networks ◽  
Energy Landscapes ◽  
Post Translational Modifications ◽  
Short Linear Motifs ◽  
Quantitative Mapping ◽  
Wide Range ◽  
Binding Peptides ◽  
Linear Motifs ◽  
Peptide Affinity

Transient, regulated binding of globular protein domains to Short Linear Motifs (SLiMs) in disordered regions of other proteins drives cellular signaling. Mapping the energy landscapes of these interactions is essential for deciphering and perturbing signaling networks but is challenging due to their weak affinities. We present a powerful technology (MRBLE-pep) that simultaneously quantifies protein binding to a library of peptides directly synthesized on beads containing unique spectral codes. Using MRBLE-pep, we systematically probe binding of calcineurin (CN), a conserved protein phosphatase essential for the immune response and target of immunosuppressants, to the PxIxIT SLiM. We discover that flanking residues and post-translational modifications critically contribute to PxIxIT-CN affinity and identify CN-binding peptides based on multiple scaffolds with a wide range of affinities. The quantitative biophysical data provided by this approach will improve computational modeling efforts, elucidate a broad range of weak protein-SLiM interactions, and revolutionize our understanding of signaling networks.

Computational Modeling of Signaling Networks for Eukaryotic Chemosensing

2009 ◽  
pp. 507-526 ◽  
Author(s):  
Martin Meier-Schellersheim ◽  
Frederick Klauschen ◽  
Bastian Angermann
Keyword(s):  
Computational Modeling ◽  
Signaling Networks

scholarly journals IGFBP-3/IGFBP-3 Receptor System as an Anti-Tumor and Anti-Metastatic Signaling in Cancer

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1261 ◽  
Author(s):  
Qing Cai ◽  
Mikhail Dozmorov ◽  
Youngman Oh
Keyword(s):  
Therapeutic Potential ◽  
Transmembrane Protein ◽  
Biological Significance ◽  
Cell Types ◽  
Receptor System ◽  
Post Translational Modifications ◽  
Major Carrier ◽  
Assay Methods ◽  
Underlying Mechanisms ◽  
Igfbp 3

Insulin-like growth factor binding protein-3 (IGFBP-3) is a p53 tumor suppressor-regulated protein and a major carrier for IGFs in circulation. Among six high-affinity IGFBPs, which are IGFBP-1 through 6, IGFBP-3 is the most extensively investigated IGFBP species with respect to its IGF/IGF-I receptor (IGF-IR)-independent biological actions beyond its endocrine/paracrine/autocrine role in modulating IGF action in cancer. Disruption of IGFBP-3 at transcriptional and post-translational levels has been implicated in the pathophysiology of many different types of cancer including breast, prostate, and lung cancer. Over the past two decades, a wealth of evidence has revealed both tumor suppressing and tumor promoting effects of IGF/IGF-IR-independent actions of IGFBP-3 depending upon cell types, post-translational modifications, and assay methods. However, IGFBP-3′s anti-tumor function has been well accepted due to identification of functional IGFBP-3-interacting proteins, putative receptors, or crosstalk with other signaling cascades. This review mainly focuses on transmembrane protein 219 (TMEM219), which represents a novel IGFBP-3 receptor mediating antitumor effect of IGFBP-3. Furthermore, this review delineates the potential underlying mechanisms involved and the subsequent biological significance, emphasizing the clinical significance of the IGFBP-3/TMEM219 axis in assessing both the diagnosis and the prognosis of cancer as well as the therapeutic potential of TMEM219 agonists for cancer treatment.

scholarly journals Post-translational modifications of EZH2 in cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhongwei Li ◽  
Minle Li ◽  
Diandian Wang ◽  
Pingfu Hou ◽  
Xintian Chen ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Therapeutic Potential ◽  
Post Translational Modifications ◽  
Polycomb Repressive Complex 2 ◽  
Binding Partners ◽  
Regulate Protein ◽  
Main Component

AbstractEnhancer of zeste homolog 2 (EZH2), as a main component of Polycomb Repressive Complex 2, catalyzes histone H3K27me3 to silence its target gene expression. EZH2 upregulation results in cancer development and poor prognosis of cancer patients. Post-translational modifications (PTMs) are important biological events in cancer progression. PTMs regulate protein conformation and diversity functions. Recently, mounting studies have demonstrated that EZH2 stability, histone methyltransferase activity, localization, and binding partners can be regulated by PTMs, including phosphorylation, O-GlcNAcylation, acetylation, methylation and ubiquitination. However, the detailed molecular mechanisms of the EZH2-PTMs and whether other types of PTMs occur in EZH2 remain largely unclear. This review presents an overview of different roles of EZH2 modification and EZH2-PTMs crosstalk during tumorigenesis and cancer metastasis. We also discussed the therapeutic potential of targeting EZH2 modifications for cancer therapy.

scholarly journals HGF/c-MET: A Promising Therapeutic Target in the Digestive System Cancers

2018 ◽  
Vol 19 (11) ◽  
pp. 3295 ◽  
Author(s):  
Hongli Zhang ◽  
Qingqing Feng ◽  
Wei-Dong Chen ◽  
Yan-Dong Wang
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Digestive System ◽  
Therapeutic Potential ◽  
Signaling Networks ◽  
Preclinical Studies ◽  
Current Review ◽  
Promising Therapeutic Target ◽  
Signaling Inhibitors ◽  
Mirna Therapeutics

The HGF/c-MET pathway is active in the development of digestive system cancers, indicating that inhibition of HGF/c-MET signaling may have therapeutic potential. Various HGF/c-MET signaling inhibitors, mainly c-MET inhibitors, have been tested in clinical trials. The observed efficacy and adverse events of some c-MET inhibitors were not very suitable for treating digestive system cancers. The development of new HGF/c-MET inhibitors in preclinical studies may bring promising treatments and synergistic combination (traditional anticancer drugs and c-MET inhibitors) strategies provided anacceptable safety and tolerability. Insights into miRNA biology and miRNA therapeutics have made miRNAs attractive tools to inhibit HGF/c-MET signaling. Recent reports show that several microRNAs participate in inhibiting HGF/c-MET signaling networks through antagonizing c-MET or HGF in digestive system cancers, and the miRNAs-HGF/c-MET axis plays crucial and novel roles for cancer treatment. In the current review, we will discuss recent findings about inhibitors of HGF/c-MET signaling in treating digestive system cancers, and how miRNAs regulate digestive system cancers via mediating HGF/c-MET pathway.

scholarly journals PS1000 POST-TRANSLATIONAL MODIFICATIONS OF PROTEIN PHOSPHATASE 2A (PP2A) IN MIXED LINEAGE LEUKEMIA (MLL)

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 450
Author(s):  
Y. Arroyo-Berdugo ◽  
A. Di Mambro ◽  
Y. Calle-Patino ◽  
B. Wrench ◽  
J. Gribben ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Mixed Lineage Leukemia ◽  
Post Translational Modifications ◽  
Phosphatase 2A

scholarly journals Post-Translational S-Nitrosylation of Proteins in Regulating Cardiac Oxidative Stress

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1051 ◽  
Author(s):  
Xiaomeng Shi ◽  
Hongyu Qiu
Keyword(s):  
Therapeutic Potential ◽  
Heart Diseases ◽  
Redox Homeostasis ◽  
Redox Status ◽  
Cardiac Protection ◽  
Cellular Functions ◽  
Post Translational Modifications ◽  
Cellular Redox ◽  
Novel Therapeutic Strategies

Like other post-translational modifications (PTMs) of proteins, S-nitrosylation has been considered a key regulatory mechanism of multiple cellular functions in many physiological and disease conditions. Emerging evidence has demonstrated that S-nitrosylation plays a crucial role in regulating redox homeostasis in the stressed heart, leading to discoveries in the mechanisms underlying the pathogenesis of heart diseases and cardiac protection. In this review, we summarize recent studies in understanding the molecular and biological basis of S-nitrosylation, including the formation, spatiotemporal specificity, homeostatic regulation, and association with cellular redox status. We also outline the currently available methods that have been applied to detect S-nitrosylation. Additionally, we synopsize the up-to-date studies of S-nitrosylation in various cardiac diseases in humans and animal models, and we discuss its therapeutic potential in cardiac protection. These pieces of information would bring new insights into understanding the role of S-nitrosylation in cardiac pathogenesis and provide novel avenues for developing novel therapeutic strategies for heart diseases.

scholarly journals CSIG-13. COMPUTATIONAL MODELING OF GLIOBLASTOMA STEM CELL SIGNALING NETWORKS

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi45-vi45
Author(s):  
Emilee Holtzapple ◽  
Natasa Miskov-Zivanov ◽  
Kenneth Jahan ◽  
Yahan Zhang ◽  
Steven Young ◽  
...  
Keyword(s):  
Stem Cell ◽  
Computational Modeling ◽  
Cell Signaling ◽  
Signaling Networks ◽  
Glioblastoma Stem Cell ◽  
Cell Signaling Networks
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