scholarly journals A widespread family of heat-resistant obscure (Hero) proteins protect against protein instability and aggregation

2019 ◽  
Author(s):  
Kotaro Tsuboyama ◽  
Tatsuya Osaki ◽  
Eriko Suzuki-Matsuura ◽  
Hiroko Kozuka-Hata ◽  
Yuki Okada ◽  
...  
Keyword(s):  
Heat Shock ◽  
High Salinity ◽  
Therapeutic Potential ◽  
Extreme Conditions ◽  
Heat Resistant ◽  
Different Types ◽  
Protein Functions ◽  
Client Proteins ◽  
Protein Instability ◽  
And Function

AbstractProteins are typically denatured and aggregated by heat. Exceptions to this principle include highly disordered and heat-resistant proteins found in extremophiles, which help these organisms tolerate extreme conditions such as drying, freezing, and high salinity. In contrast, the functions of heat-soluble proteins in non-extremophilic organisms including humans remain largely unexplored. Here we report that heat-resistant obscure (Hero) proteins, which remain soluble after boiling at 95°C, are widespread in Drosophila and humans. Hero proteins are hydrophilic and highly charged, and function to stabilize various “client” proteins, protecting them from denaturation even under stress conditions such as heat shock, desiccation, and exposure to organic solvents. Hero proteins can also block several different types of pathological protein aggregations in cells and in Drosophila strains that model neurodegenerative diseases. Moreover, Hero proteins can extend lifespan of Drosophila. Our study reveals that organisms naturally use Hero proteins as molecular shields to stabilize protein functions, highlighting their biotechnological and therapeutic potential.

scholarly journals A Brain Penetrating Heat-Shock Protein 90 Inhibitor NXD30001 Inhibits Glioblastoma as a Monotherapy or in Combination With Radiation

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Hao Chen ◽  
Jialiang Wang ◽  
Hengli Tian
Keyword(s):  
Stem Cells ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Median Survival ◽  
Therapeutic Potential ◽  
Heat Shock Protein 90 ◽  
Tumor Bearing ◽  
Client Proteins

Abstract INTRODUCTION It has been increasingly recognized that glioblastoma multiforme (GBM) is a highly heterogeneous disease, which is initiated and sustained by molecular alterations in an array of signal transduction pathways. Heat-shock protein 90 (Hsp90) is a molecular chaperone to be critically implicated in folding and activation of a diverse group of client proteins, many of which are key regulators of important glioblastoma biology. METHODS To determine the therapeutic potential of targeting Hsp90 in glioblastoma, we assessed the anti-neoplastic efficacy of NXD30001, a brain-penetrating Hsp90 inhibitor as a monotherapy or in combination with radiation, both in Vitro and in Vivo. RESULTS Our results demonstrated that NXD30001 potently inhibited neurosphere formation, growth and survival of CD133 + glioblastoma stem cells (GSCs) with the half maximal inhibitory concentrations (IC50) at low nanomolar concentrations. At suboptimal concentrations, inhibition of Hsp90 did not exert cytotoxic activity but rather increased radiosensitivity in GSCs. CD133- GBM cells were less sensitive and not radiosensitized by NXD30001. In lines with its cytotoxic and radiosensitizing effects, NXD30001 dose-dependently decreased phosphorylation protein levels of multiple Hsp90 client proteins, including those playing key roles in GSCs, such as EGFR, Akt, c-Myc, and Notch1. In addition, combining NXD30001 with radiation could impair DNA damage response and ER stress response to induce apoptosis of GSCs. Treatment of orthotopic glioblastoma tumors with NXD30001 extended median survival of tumor-bearing mice by approximately 20% (treated 37 days vs vehicle 31 d, P = .0026). Radiation alone increased median survival of tumor-bearing mice from 31 to 38 d, combination with NXD30001 further extended survival to 43 d (P = .0089). CONCLUSION Our results suggest that GBM stem cells (CD133+) are more sensitive to NXD30001 than non-stem GBM cells (CD133-). Furthermore, combination NXD30001 with radiation significantly inhibits GBM progression than use it as a monotherapy by targeting GSCs.

scholarly journals Posttranslational modifications in proteins: resources, tools and prediction methods

Database ◽  
2021 ◽  
Author(s):  
Shahin Ramazi ◽  
Javad Zahiri
Keyword(s):  
Computational Methods ◽  
Posttranslational Modifications ◽  
Side Chain ◽  
Amino Acid Side Chain ◽  
Cellular Processes ◽  
Online Databases ◽  
Different Types ◽  
Protein Functions ◽  
And Function ◽  
Molecular Regulatory Mechanisms

Abstract Posttranslational modifications (PTMs) refer to amino acid side chain modification in some proteins after their biosynthesis. There are more than 400 different types of PTMs affecting many aspects of protein functions. Such modifications happen as crucial molecular regulatory mechanisms to regulate diverse cellular processes. These processes have a significant impact on the structure and function of proteins. Disruption in PTMs can lead to the dysfunction of vital biological processes and hence to various diseases. High-throughput experimental methods for discovery of PTMs are very laborious and time-consuming. Therefore, there is an urgent need for computational methods and powerful tools to predict PTMs. There are vast amounts of PTMs data, which are publicly accessible through many online databases. In this survey, we comprehensively reviewed the major online databases and related tools. The current challenges of computational methods were reviewed in detail as well.

scholarly journals Protein prenylation and Hsp40 in thermotolerance of Plasmodium falciparum malaria parasites

2019 ◽  
Author(s):  
Emily S. Mathews ◽  
Andrew J. Jezewski ◽  
Audrey R. Odom John
Keyword(s):  
Plasmodium Falciparum ◽  
Heat Shock ◽  
Malaria Parasite ◽  
Plasmodium Falciparum Malaria ◽  
Complex Life Cycle ◽  
Protein Prenylation ◽  
Membrane Attachment ◽  
Client Proteins ◽  
Essential Function ◽  
And Function

AbstractDuring its complex life cycle, the malaria parasite survives dramatic changes in environmental temperature. Protein prenylation is required during asexual replication of Plasmodium falciparum, and heat shock protein 40 (HSP40; PF3D7_1437900) is post-translationally modified with a 15-carbon farnesyl isoprenyl group. In other organisms, farnesylation of Hsp40 orthologs controls its localization and function, including temperature stress survival. In this work, we find that plastidial isopentenyl pyrophosphate (IPP) synthesis and protein farnesylation are required for malaria parasite survival after cold and heat shock. Furthermore, loss of HSP40 farnesylation alters its membrane attachment and interaction with proteins involved in crucial biological processes, such as glycolysis and cytoskeletal organization. Together, this work reveals that farnesylation of HSP40 in P. falciparum is a novel essential function of plastidial isoprenoid biosynthesis. We propose a model by which farnesyl-HSP40 promotes parasite thermotolerance and facilitates vesicular trafficking through its interaction with client proteins.

scholarly journals Pathology-Dependent Effects Linked to Small Heat Shock Proteins Expression: An Update

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-19 ◽  
Author(s):  
A.-P. Arrigo
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Inflammatory Diseases ◽  
Small Heat Shock Proteins ◽  
Cell Degeneration ◽  
Cellular Protection ◽  
Different Types ◽  
Small Hsps ◽  
Client Proteins ◽  
Shock Proteins

Small heat shock proteins (small Hsps) are stress-induced molecular chaperones that act as holdases towards polypeptides that have lost their folding in stress conditions or consequently of mutations in their coding sequence. A cellular protection against the deleterious effects mediated by damaged proteins is thus provided to cells. These chaperones are also highly expressed in response to protein conformational and inflammatory diseases and cancer pathologies. Through specific and reversible modifications in their phospho-oligomeric organization, small Hsps can chaperone appropriate client proteins in order to provide cells with resistance to different types of injuries or pathological conditions. By helping cells to better cope with their pathological status, their expression can be either beneficial, such as in diseases characterized by pathological cell degeneration, or deleterious when they are required for tumor cell survival. Moreover, small Hsps are actively released by cells and can act as immunogenic molecules that have dual effects depending on the pathology. The cellular consequences linked to their expression levels and relationships with other Hsps as well as therapeutic strategies are discussed in view of their dynamic structural organization required to interact with specific client polypeptides.

Chaperonin as the normal controls and pathological anti-stress response in the human reproductive system

2016 ◽  
pp. 126-129
Author(s):  
M. Makarenko ◽  
◽  
D. Hovsyeyev ◽  
L. Sydoryk ◽  
◽  
...  
Keyword(s):  
Reproductive System ◽  
Stress Proteins ◽  
Physiological Stress ◽  
Protein Complexes ◽  
Reproductive Function ◽  
Intercellular Signaling ◽  
Toll Like Receptors ◽  
Wide Range ◽  
Protein Functions ◽  
And Function

Different kinds of physiological stress cause mass changes in the cells, including the changes in the structure and function of the protein complexes and in separate molecules. The protein functions is determined by its folding (the spatial conclusion), which depends on the functioning of proteins of thermal shock- molecular chaperons (HSPs) or depends on the stress proteins, that are high-conservative; specialized proteins that are responsible for the correct proteinaceous folding. The family of the molecular chaperones/ chaperonins/ Hsp60 has a special place due to the its unique properties of activating the signaling cascades through the system of Toll-like receptors; it also stimulates the cells to produce anti- inflammatory cytokines, defensins, molecules of cell adhesion and the molecules of MHC; it functions as the intercellular signaling molecule. The pathological role of Hsp60 is established in a wide range of illnesses, from diabetes to atherosclerosis, where Hsp60 takes part in the regulation of both apoptosis and the autoimmune processes. The presence of the HSPs was found in different tissues that are related to the reproductive system. Key words: molecular chaperons (HSPs), Toll-like receptors, reproductive function, natural auto antibody.

Sam Domains in Multiple Diseases

2020 ◽  
Vol 27 (3) ◽  
pp. 450-476 ◽  
Author(s):  
Marian Vincenzi ◽  
Flavia Anna Mercurio ◽  
Marilisa Leone
Keyword(s):  
Disease Onset ◽  
Protein Domain ◽  
Sam Domain ◽  
Different Types ◽  
Protein Functions ◽  
Helical Protein ◽  
The Many ◽  
Novel Therapeutic Strategies ◽  
Novel Drug ◽  
Pathological Event

Background: The sterile alpha motif (Sam) domain is a small helical protein module, able to undergo homo- and hetero-oligomerization, as well as polymerization, thus forming different types of protein architectures. A few Sam domains are involved in pathological processes and consequently, they represent valuable targets for the development of new potential therapeutic routes. This study intends to collect state-of-the-art knowledge on the different modes by which Sam domains can favor disease onset and progression. Methods: This review was build up by searching throughout the literature, for: a) the structural properties of Sam domains, b) interactions mediated by a Sam module, c) presence of a Sam domain in proteins relevant for a specific disease. Results: Sam domains appear crucial in many diseases including cancer, renal disorders, cataracts. Often pathologies are linked to mutations directly positioned in the Sam domains that alter their stability and/or affect interactions that are crucial for proper protein functions. In only a few diseases, the Sam motif plays a kind of "side role" and cooperates to the pathological event by enhancing the action of a different protein domain. Conclusion: Considering the many roles of the Sam domain into a significant variety of diseases, more efforts and novel drug discovery campaigns need to be engaged to find out small molecules and/or peptides targeting Sam domains. Such compounds may represent the pillars on which to build novel therapeutic strategies to cure different pathologies.

Apigenin Alleviates Renal Fibroblast Activation through AMPK and ERK Signaling Pathways In Vitro

2020 ◽  
Vol 21 (11) ◽  
pp. 1107-1118
Author(s):  
Ningning Li ◽  
Zhan Wang ◽  
Tao Sun ◽  
Yanfei Lei ◽  
Xianghua Liu ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Protective Role ◽  
Fibroblast Proliferation ◽  
Fibroblast Activation ◽  
And Function ◽  
Activated Fibroblasts ◽  
Tgf Β1

Objective: Renal fibrosis is a common pathway leading to the progression of chronic kidney disease. Activated fibroblasts contribute remarkably to the development of renal fibrosis. Although apigenin has been demonstrated to play a protective role from fibrotic diseases, its pharmacological effect on renal fibroblast activation remains largely unknown. Materials and Methods: Here, we examined the functional role of apigenin in the activation of renal fibroblasts response to transforming growth factor (TGF)-β1 and its potential mechanisms. Cultured renal fibroblasts (NRK-49F) were exposed to apigenin (1, 5, 10 and 20 μM), followed by the stimulation of TGF-β1 (2 ng/mL) for 24 h. The markers of fibroblast activation were determined. In order to confirm the anti-fibrosis effect of apigenin, the expression of fibrosis-associated genes in renal fibroblasts was assessed. As a consequence, apigenin alleviated fibroblast proliferation and fibroblastmyofibroblast differentiation induced by TGF-β1. Result: Notably, apigenin significantly inhibited the fibrosis-associated genes expression in renal fibroblasts. Moreover, apigenin treatment significantly increased the phosphorylation of AMP-activated protein kinase (AMPK). Apigenin treatment also obviously reduced TGF-β1 induced phosphorylation of ERK1/2 but not Smad2/3, p38 and JNK MAPK in renal fibroblasts. Conclusion: In a summary, these results indicate that apigenin inhibits renal fibroblast proliferation, differentiation and function by AMPK activation and reduced ERK1/2 phosphorylation, suggesting it could be an attractive therapeutic potential for the treatment of renal fibrosis.

Strategies for Oral Delivery of Metal-Saturated Lactoferrin

2019 ◽  
Vol 20 (11) ◽  
pp. 1046-1051 ◽  
Author(s):  
Przemysław Gajda-Morszewski ◽  
Klaudyna Śpiewak-Wojtyła ◽  
Maria Oszajca ◽  
Małgorzata Brindell
Keyword(s):  
Biological Activity ◽  
Oral Delivery ◽  
Therapeutic Potential ◽  
Structure And Function ◽  
The Difference ◽  
And Function ◽  
First Time

Lactoferrin was isolated and purified for the first time over 50-years ago. Since then, extensive studies on the structure and function of this protein have been performed and the research is still being continued. In this mini-review we focus on presenting recent scientific efforts towards the elucidation of the role and therapeutic potential of lactoferrin saturated with iron(III) or manganese(III) ions. The difference in biological activity of metal-saturated lactoferrin vs. the unmetalated one is emphasized. The strategies for oral delivery of lactoferrin, are also reviewed, with particular attention to the metalated protein.

Classic and Novel Signaling Pathways Involved in Cancer: Targeting the NF-κB and Syk Signaling Pathways

2019 ◽  
Vol 14 (3) ◽  
pp. 219-225 ◽  
Author(s):  
Cong Tang ◽  
Guodong Zhu
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Transmembrane Receptors ◽  
Biological Responses ◽  
Different Types

The nuclear factor kappa B (NF-κB) consists of a family of transcription factors involved in the regulation of a wide variety of biological responses. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation. Therefore, we made a review of the diverse molecular mechanisms by which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. We also discussed various pharmacological approaches employed to target the deregulated NF-κB signaling pathway and their possible therapeutic potential in cancer therapy. Moreover, Syk (Spleen tyrosine kinase), non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which can also activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in the presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved in NF-κB and Syk signaling and then raise some possibilities for cancer therapy.

scholarly journals Thiol-based switching mechanisms of stress-sensing chaperones

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Kathrin Ulrich ◽  
Blanche Schwappach ◽  
Ursula Jakob
Keyword(s):  
Oxidative Stress ◽  
Environmental Changes ◽  
Stress Conditions ◽  
Stress Exposure ◽  
Atp Levels ◽  
Protein Functions ◽  
Activation Mechanisms ◽  
Client Proteins ◽  
Stress Sensing ◽  
Redox Switches

AbstractThiol-based redox switches evolved as efficient post-translational regulatory mechanisms that enable individual proteins to rapidly respond to sudden environmental changes. While some protein functions need to be switched off to save resources and avoid potentially error-prone processes, protective functions become essential and need to be switched on. In this review, we focus on thiol-based activation mechanisms of stress-sensing chaperones. Upon stress exposure, these chaperones convert into high affinity binding platforms for unfolding proteins and protect cells against the accumulation of potentially toxic protein aggregates. Their chaperone activity is independent of ATP, a feature that becomes especially important under oxidative stress conditions, where cellular ATP levels drop and canonical ATP-dependent chaperones no longer operate. Vice versa, reductive inactivation and substrate release require the restoration of ATP levels, which ensures refolding of client proteins by ATP-dependent foldases. We will give an overview over the different strategies that cells evolved to rapidly increase the pool of ATP-independent chaperones upon oxidative stress and provide mechanistic insights into how stress conditions are used to convert abundant cellular proteins into ATP-independent holding chaperones.

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