Insights into adaptor binding to the AAA protein p97

2008 ◽  
Vol 36 (1) ◽  
pp. 62-67 ◽  
Author(s):  
Heidi O. Yeung ◽  
Patrik Kloppsteck ◽  
Hajime Niwa ◽  
Rivka L. Isaacson ◽  
Steve Matthews ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Biological Activities ◽  
Binding Motif ◽  
Binding Modes ◽  
Aaa Atpase ◽  
Essential Component ◽  
Cellular Pathways ◽  
Aaa Protein ◽  
Structural Homologues ◽  
Binding Mechanisms

The AAA (ATPase associated with various cellular activities) p97 [also known as VCP (valosin-containing protein)] participates in numerous biological activities and is an essential component of the ubiquitin signalling pathway. A plethora of adaptors have been reported for p97, and increasing evidence is suggesting that it is through adaptor binding that p97 is diverted into different cellular pathways. Studying the interaction between p97 and its adaptors is therefore crucial to our understanding of the physiological roles of the protein. The interactions between p97 and the PUB [PNGase (peptide N-glycosidase)/ubiquitin-associated] domain of PNGase, the UBX (ubiquitin regulatory X) domain of p47, and the UBD (ubiquitin D) domain of Npl4 have been structurally characterized. UBX and UBD are structural homologues that share similar p97-binding modes; it is plausible that other proteins that contain a UBX/UBX-like domain also interact with p97 via similar mechanisms. In addition, several short p97-interacting motifs, such as VBM (VCP-binding motif), VIM (VCP-interacting motif) and SHP, have been identified recently and are also shared between p97 adaptors, hinting that proteins possessing the same p97-binding motif might also share common p97-binding mechanisms. In this review, we aim to summarize our current knowledge on adaptor binding to p97.

Recent Advances of In-Silico Modeling of Potent Antagonists for the Adenosine Receptors

2019 ◽  
Vol 25 (7) ◽  
pp. 750-773 ◽  
Author(s):  
Pabitra Narayan Samanta ◽  
Supratik Kar ◽  
Jerzy Leszczynski
Keyword(s):  
Drug Targets ◽  
Biological Activities ◽  
Scoring Function ◽  
Md Simulations ◽  
Energy Calculation ◽  
Binding Modes ◽  
Macromolecular Systems ◽  
In Silico Modeling ◽  
Mathematical Algorithms ◽  
The Impact

The rapid advancement of computer architectures and development of mathematical algorithms offer a unique opportunity to leverage the simulation of macromolecular systems at physiologically relevant timescales. Herein, we discuss the impact of diverse structure-based and ligand-based molecular modeling techniques in designing potent and selective antagonists against each adenosine receptor (AR) subtype that constitutes multitude of drug targets. The efficiency and robustness of high-throughput empirical scoring function-based approaches for hit discovery and lead optimization in the AR family are assessed with the help of illustrative examples that have led to nanomolar to sub-micromolar inhibition activities. Recent progress in computer-aided drug discovery through homology modeling, quantitative structure-activity relation, pharmacophore models, and molecular docking coupled with more accurate free energy calculation methods are reported and critically analyzed within the framework of structure-based virtual screening of AR antagonists. Later, the potency and applicability of integrated molecular dynamics (MD) methods are addressed in the context of diligent inspection of intricated AR-antagonist binding processes. MD simulations are exposed to be competent for studying the role of the membrane as well as the receptor flexibility toward the precise evaluation of the biological activities of antagonistbound AR complexes such as ligand binding modes, inhibition affinity, and associated thermodynamic and kinetic parameters.

The DEAH helicase DHX36 and its role in G-quadruplex-dependent processes

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Philipp Schult ◽  
Katrin Paeschke
Keyword(s):  
Current Knowledge ◽  
Future Research ◽  
Transcriptional Level ◽  
Cellular Functions ◽  
Multiple Functions ◽  
Open Questions ◽  
G Quadruplex ◽  
Cellular Pathways ◽  
Nucleic Acid Structures ◽  
Dependent Processes

AbstractDHX36 is a member of the DExD/H box helicase family, which comprises a large number of proteins involved in various cellular functions. Recently, the function of DHX36 in the regulation of G-quadruplexes (G4s) was demonstrated. G4s are alternative nucleic acid structures, which influence many cellular pathways on a transcriptional and post-transcriptional level. In this review we provide an overview of the current knowledge about DHX36 structure, substrate specificity, and mechanism of action based on the available models and crystal structures. Moreover, we outline its multiple functions in cellular homeostasis, immunity, and disease. Finally, we discuss the open questions and provide potential directions for future research.

scholarly journals Melatonin in Cancer Treatment: Current Knowledge and Future Opportunities

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2506
Author(s):  
Wamidh H. Talib ◽  
Ahmad Riyad Alsayed ◽  
Alaa Abuawad ◽  
Safa Daoud ◽  
Asma Ismail Mahmod
Keyword(s):  
Clinical Trials ◽  
Current Knowledge ◽  
Biological Activities ◽  
Experimental Studies ◽  
Therapeutic Effects ◽  
Cell Proliferation Inhibition ◽  
Different Types ◽  
Solid Foundation

Melatonin is a pleotropic molecule with numerous biological activities. Epidemiological and experimental studies have documented that melatonin could inhibit different types of cancer in vitro and in vivo. Results showed the involvement of melatonin in different anticancer mechanisms including apoptosis induction, cell proliferation inhibition, reduction in tumor growth and metastases, reduction in the side effects associated with chemotherapy and radiotherapy, decreasing drug resistance in cancer therapy, and augmentation of the therapeutic effects of conventional anticancer therapies. Clinical trials revealed that melatonin is an effective adjuvant drug to all conventional therapies. This review summarized melatonin biosynthesis, availability from natural sources, metabolism, bioavailability, anticancer mechanisms of melatonin, its use in clinical trials, and pharmaceutical formulation. Studies discussed in this review will provide a solid foundation for researchers and physicians to design and develop new therapies to treat and prevent cancer using melatonin.

scholarly journals Chemistry and Biology of Essential Oils of GenusBoswellia

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Hidayat Hussain ◽  
Ahmed Al-Harrasi ◽  
Ahmed Al-Rawahi ◽  
Javid Hussain
Keyword(s):  
Essential Oils ◽  
Current Knowledge ◽  
Biological Activities ◽  
Ethanolic Extract ◽  
Quantitative Composition ◽  
Volatile Constituents ◽  
Traditional Medicines ◽  
Qualitative And Quantitative ◽  
Synthetic Drugs ◽  
Explicit Consideration

The properties ofBoswelliaplants have been exploited for millennia in the traditional medicines of Africa, China, and especially in the Indian Ayurveda. In Western countries, the advent of synthetic drugs has obscured the pharmaceutical use ofBoswellia, until it was reported that an ethanolic extract exerts anti-inflammatory and antiarthritic effects. Frankincense was commonly used for medicinal purposes. This paper aims to provide an overview of current knowledge of the volatile constituents of frankincense, with explicit consideration concerning the diverseBoswelliaspecies. Altogether, more than 340 volatiles inBoswelliahave been reported in the literature. In particular, a broad diversity has been found in the qualitative and quantitative composition of the volatiles with respect to different varieties ofBoswellia. A detailed discussion of the various biological activities ofBoswelliafrankincense is also presented.

scholarly journals Cytoplasmic Recycling of 60S Preribosomal Factors Depends on the AAA Protein Drg1

2007 ◽  
Vol 27 (19) ◽  
pp. 6581-6592 ◽  
Author(s):  
Brigitte Pertschy ◽  
Cosmin Saveanu ◽  
Gertrude Zisser ◽  
Alice Lebreton ◽  
Martin Tengg ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Nuclear Export ◽  
Ribosome Biogenesis ◽  
Dominant Negative ◽  
Cytoplasmic Localization ◽  
Atpase Domain ◽  
Aaa Atpase ◽  
Cytoplasmic Accumulation ◽  
Functional Inactivation ◽  
Aaa Protein

ABSTRACT Allelic forms of DRG1/AFG2 confer resistance to the drug diazaborine, an inhibitor of ribosome biogenesis in Saccharomyces cerevisiae. Our results show that the AAA-ATPase Drg1 is essential for 60S maturation and associates with 60S precursor particles in the cytoplasm. Functional inactivation of Drg1 leads to an increased cytoplasmic localization of shuttling pre-60S maturation factors like Rlp24, Arx1, and Tif6. Surprisingly, Nog1, a nuclear pre-60S factor, was also relocalized to the cytoplasm under these conditions, suggesting that it is a previously unsuspected shuttling preribosomal factor that is exported with the precursor particles and very rapidly reimported. Proteins that became cytoplasmic under drg1 mutant conditions were blocked on pre-60S particles at a step that precedes the association of Rei1, a later-acting preribosomal factor. A similar cytoplasmic accumulation of Nog1 and Rlp24 in pre-60S-bound form could be seen after overexpression of a dominant-negative Drg1 variant mutated in the D2 ATPase domain. We conclude that the ATPase activity of Drg1 is required for the release of shuttling proteins from the pre-60S particles shortly after their nuclear export. This early cytoplasmic release reaction defines a novel step in eukaryotic ribosome maturation.

scholarly journals Subcellular Targeting of p33ING1b by Phosphorylation-Dependent 14-3-3 Binding Regulates p21WAF1 Expression

2006 ◽  
Vol 26 (8) ◽  
pp. 2947-2954 ◽  
Author(s):  
Wei Gong ◽  
Michael Russell ◽  
Keiko Suzuki ◽  
Karl Riabowol
Keyword(s):  
Kinase Inhibitor ◽  
Biological Activities ◽  
Ectopic Expression ◽  
Growth Stress ◽  
Nuclear Localization Sequence ◽  
Binding Motif ◽  
Subcellular Targeting ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cargo Proteins ◽  
Localization Sequence

ABSTRACT ING1 is a type II tumor suppressor that affects cell growth, stress signaling, apoptosis, and DNA repair by altering chromatin structure and regulating transcription. Decreased ING1 expression is seen in several human cancers, and mislocalization has been noted in diverse types of cancer cells. Aberrant targeting may, therefore, functionally inactivate ING1. Bioinformatics analysis identified a sequence between the nuclear localization sequence and plant homeodomain domains of ING1 that closely matched the binding motif of 14-3-3 proteins that target cargo proteins to specific subcellular locales. We find that the widely expressed p33ING1b splicing isoform of ING1 interacts with members of the 14-3-3 family of proteins and that this interaction is regulated by the phosphorylation status of ING1. 14-3-3 binding resulted in significant amounts of p33ING1b protein being tethered in the cytoplasm. As shown previously, ectopic expression of p33ING1b increased levels of the p21Waf1 cyclin-dependent kinase inhibitor upon UV-induced DNA damage. Overexpression of 14-3-3 inhibited the up-regulation of p21Waf1 by p33ING1b, consistent with the idea that mislocalization blocks at least one of ING1's biological activities. These data support the idea that the 14-3-3 proteins play a crucial role in regulating the activity of p33ING1b by directing its subcellular localization.

scholarly journals Variations in Essential Oil Chemical Composition and Biological Activities of Cryptomeria japonica (Thunb. ex L.f.) D. Don from Different Geographical Origins—A Critical Review

2021 ◽  
Vol 11 (23) ◽  
pp. 11097
Author(s):  
Ana Lima ◽  
Filipe Arruda ◽  
Jorge Medeiros ◽  
José Baptista ◽  
João Madruga ◽  
...  
Keyword(s):  
Chemical Composition ◽  
Cryptomeria Japonica ◽  
Current Knowledge ◽  
Biological Activities ◽  
Forest Biomass ◽  
Biological Properties ◽  
Added Value ◽  
Endogenous Factors ◽  
Wood Processing ◽  
Social Environmental

The scientific community is paying increasing attention to plant waste valorization, and also to “greener” practices in the agriculture, food and cosmetic sectors. In this context, unused forest biomass (e.g., leaves, seed cones, branches/twigs, bark and sapwood) of Cryptomeria japonica, a commercially important tree throughout Asia and the Azores Archipelago (Portugal), is currently waste/by-products of wood processing that can be converted into eco-friendly and high added-value products, such as essential oils (EOs), with social, environmental and economic impacts. Plant-derived EOs are complex mixtures of metabolites, mostly terpenes and terpenoids, with valuable bioactivities (e.g., antioxidant, anti-inflammatory, anticancer, neuroprotective, antidepressant, antimicrobial, antiviral and pesticide), which can find applications in several industries, such as pharmaceutical, medical, aromatherapy, food, cosmetic, perfumery, household and agrochemical (e.g., biopesticides), with manifold approaches. The EOs components are also of value for taxonomic investigations. It is known that the variation in EOs chemical composition and, consequently, in their biological activities and commercial use, is due to different exogenous and endogenous factors that can lead to ecotypes or chemotypes in the same plant species. The present paper aims to provide an overview of the chemical composition, biological properties and proposals of valorization of C. japonica EO from several countries, and also to indicate gaps in the current knowledge.

scholarly journals The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises

2021 ◽  
Vol 23 (1) ◽  
pp. 430
Author(s):  
Ángel Ortega ◽  
Ivana Vera ◽  
Maria P. Diaz ◽  
Carla Navarro ◽  
Milagros Rojas ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Signaling Pathway ◽  
Growth Regulation ◽  
Current Knowledge ◽  
Biological Effects ◽  
Critical Role ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Tumor Resistance ◽  
Therapeutic Alternatives

The yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, members of the Hippo signaling pathway, which play a critical role in cell growth regulation, embryonic development, regeneration, proliferation, and cancer origin and progression. The mechanism involves the nuclear binding of the un-phosphorylated YAP/TAZ complex to release the transcriptional enhanced associate domain (TEAD) from its repressors. The active ternary complex is responsible for the aforementioned biological effects. Overexpression of YAP/TAZ has been reported in cancer stem cells and tumor resistance. The resistance involves chemotherapy, targeted therapy, and immunotherapy. This review provides an overview of YAP/TAZ pathways’ role in carcinogenesis and tumor microenvironment. Potential therapeutic alternatives are also discussed.

scholarly journals PHARMACEUTICAL POTENTIAL OF LABORATORY GROWN CULTURES OF BLUE-GREEN ALGAE: A COMPREHENSIVE REVIEW AND FUTURE POSSIBILITIES

2021 ◽  
Vol 9 (5) ◽  
pp. 543-571
Author(s):  
Ritu Chauhan ◽  
◽  
Abhishek Chauhan ◽  
Ashutosh Tripathi ◽  
Anuj Ranjan ◽  
...  
Keyword(s):  
Green Algae ◽  
Bioactive Compounds ◽  
Current Knowledge ◽  
Biological Activities ◽  
Biologically Active ◽  
Primary And Secondary Metabolites ◽  
Blue Green Algae ◽  
Green Algal ◽  
Algal Group ◽  
Diverse Application

COVID-19 pandemic has taught the world researchers the urgent need for new sources and novel pharmaceuticals not only for existing diseases but also for both seasonal epidemics and future pandemics. Pharmaceutical drug discoveries for the past fifty years depended deeply on the procedure of empirical transmission of a huge number of pure bioactive compounds to provide new leads. The screening of extracts or isolating compounds is a common way to discover novel biologically active molecules. Most of the valuable Blue-Green algal metabolites are concentrated in their biomass. For existence in nature, Blue-Green algae (BGA) secrete and contain various organic substances like proteins, fatty acids, vitamins, pigments, primary and secondary metabolites, and these compounds are explored for potential biological activities such as antibacterial, antifungal, antiviral (including the anti-SARS-CoV-2 virus that causes COVID-19), anticancer, antioxidant, antidiabetic, protease inhibitory activity, anti-inflammatory activity, etc. Due to their diverse application, pharmaceutical companies have shown commercial interest in the Blue-green algal group for the discovery and development of novel molecules to combat deadly diseases for the benefit of society and mankind. The current review paper highlights and discusses the diverse pharmaceutical potential of laboratory-grown cultures of BGA along with comprehensive and current knowledge on bioactive compounds discovered by researchers globally.

scholarly journals Dual Role of the PTPN13 Tyrosine Phosphatase in Cancer

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1659
Author(s):  
Soha Mcheik ◽  
Leticia Aptecar ◽  
Peter Coopman ◽  
Véronique D’Hondt ◽  
Gilles Freiss
Keyword(s):  
Current Knowledge ◽  
Biological Activities ◽  
Tyrosine Phosphatase ◽  
Tumor Formation ◽  
Receptor Protein ◽  
Cell Junction ◽  
Future Research ◽  
Tyrosine Kinase Signaling ◽  
Cancer Types ◽  
Oncogenic Protein

In this review article, we present the current knowledge on PTPN13, a class I non-receptor protein tyrosine phosphatase identified in 1994. We focus particularly on its role in cancer, where PTPN13 acts as an oncogenic protein and also a tumor suppressor. To try to understand these apparent contradictory functions, we discuss PTPN13 implication in the FAS and oncogenic tyrosine kinase signaling pathways and in the associated biological activities, as well as its post-transcriptional and epigenetic regulation. Then, we describe PTPN13 clinical significance as a prognostic marker in different cancer types and its impact on anti-cancer treatment sensitivity. Finally, we present future research axes following recent findings on its role in cell junction regulation that implicate PTPN13 in cell death and cell migration, two major hallmarks of tumor formation and progression.

Sign in / Sign up

Export Citation Format

Share Document