scholarly journals The Complex Phosphorylation Patterns that Regulate the Activity of Hsp70 and Its Cochaperones

2019 ◽  
Vol 20 (17) ◽  
pp. 4122 ◽  
Author(s):  
Velasco ◽  
Dublang ◽  
Moro ◽  
Muga
Keyword(s):  
Biological Activity ◽  
Molecular Chaperones ◽  
Acute Stress ◽  
Phosphorylation Sites ◽  
Native Structure ◽  
Post Translational Modifications ◽  
Cytotoxic Cells ◽  
Functional Consequences ◽  
Client Proteins ◽  
Human Hsp70

Proteins must fold into their native structure and maintain it during their lifespan to display the desired activity. To ensure proper folding and stability, and avoid generation of misfolded conformations that can be potentially cytotoxic, cells synthesize a wide variety of molecular chaperones that assist folding of other proteins and avoid their aggregation, which unfortunately is unavoidable under acute stress conditions. A protein machinery in metazoa, composed of representatives of the Hsp70, Hsp40, and Hsp110 chaperone families, can reactivate protein aggregates. We revised herein the phosphorylation sites found so far in members of these chaperone families and the functional consequences associated with some of them. We also discuss how phosphorylation might regulate the chaperone activity and the interaction of human Hsp70 with its accessory and client proteins. Finally, we present the information that would be necessary to decrypt the effect that post-translational modifications, and especially phosphorylation, could have on the biological activity of the Hsp70 system, known as the “chaperone code”.

scholarly journals Phosphorylation in the Charged Linker Modulates Interactions and Secretion of Hsp90β

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1701
Author(s):  
Lorenz Weidenauer ◽  
Manfredo Quadroni
Keyword(s):  
Mass Spectrometry ◽  
K562 Cells ◽  
Phosphorylation Sites ◽  
Activity Regulation ◽  
Wild Type ◽  
Post Translational Modifications ◽  
Linker Region ◽  
Cellular Processes ◽  
Tryptic Cleavage ◽  
Client Proteins

Hsp90β is a major chaperone involved in numerous cellular processes. Hundreds of client proteins depend on Hsp90β for proper folding and/or activity. Regulation of Hsp90β is critical to coordinate its tasks and is mediated by several post-translational modifications. Here, we focus on two phosphorylation sites located in the charged linker region of human Hsp90β, Ser226 and Ser255, which have been frequently reported but whose function remains unclear. Targeted measurements by mass spectrometry indicated that intracellular Hsp90β is highly phosphorylated on both sites (>90%). The level of phosphorylation was unaffected by various stresses (e.g., heat shock, inhibition with drugs) that impact Hsp90β activity. Mutating the two serines to alanines increased the amount of proteins interacting with Hsp90β globally and increased the sensitivity to tryptic cleavage in the C-terminal domain. Further investigation revealed that phosphorylation on Ser255 and to a lesser extent on Ser226 is decreased in the conditioned medium of cultured K562 cells, and that a non-phosphorylatable double alanine mutant was secreted more efficiently than the wild type. Overall, our results show that phosphorylation events in the charged linker regulate both the interactions of Hsp90β and its secretion, through changes in the conformation of the chaperone.

Cotranslational folding of proteins

1995 ◽  
Vol 73 (11-12) ◽  
pp. 1217-1220 ◽  
Author(s):  
Vyacheslav A. Kolb ◽  
Eugeny V. Makeyev ◽  
Aigar Kommer ◽  
Alexander S. Spirin
Keyword(s):  
Protein Folding ◽  
Biological Activity ◽  
Molecular Chaperones ◽  
Mature Protein ◽  
Native Structure ◽  
Folding Process ◽  
Cotranslational Folding

Many unfolded polypeptides are capable of refolding into their native structure upon the removal of the denaturant. However, the folding of the mature protein during renaturation does not accurately reflect the folding process of nascent proteins in the interior of the cell. This view resulted from the discovery of molecular chaperones known to modulate protein folding. Recent publications discussing the possible role and mechanisms of chaperone action suggest that folding in vivo may be a posttranslational process. Here we discuss data that indicate the final native structure and biological activity can be attainted by nascent protein on the ribosome, thus supporting the cotranslational folding hypothesis.Key words: nacent peptide, globin, luciferase, folding.

Survival of native structure and biological activity in fibronectin pasteurized in the presence of sucrose

1982 ◽  
Vol 27 (3) ◽  
pp. 286-296 ◽  
Author(s):  
Donald G. Wallace ◽  
Phillip M. Schneider ◽  
Ann M. Meunier ◽  
John L. Lundblad
Keyword(s):  
Biological Activity ◽  
Native Structure

scholarly journals Morphological Alterations and Stress Protein Variations in Lung Biopsies Obtained from Autopsies of COVID-19 Subjects

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3136
Author(s):  
Rosario Barone ◽  
Antonella Marino Gammazza ◽  
Letizia Paladino ◽  
Alessandro Pitruzzella ◽  
Giulio Spinoso ◽  
...  
Keyword(s):  
Molecular Chaperones ◽  
Histological Analysis ◽  
Stress Protein ◽  
Control Group ◽  
Post Translational Modifications ◽  
Morphological Alterations ◽  
New Biomarkers ◽  
Lung Biopsies ◽  
Cell Stress Response ◽  
Shock Proteins

Molecular chaperones, many of which are heat shock proteins, play a role in cell stress response and regulate the immune system in various ways, such as in inflammatory/autoimmune reactions. It would be interesting to study the involvement of these molecules in the damage done to COVID-19-infected lungs. In our study, we performed a histological analysis and an immunomorphological evaluation on lung samples from subjects who succumbed to COVID-19 and subjects who died from other causes. We also assessed Hsp60 and Hsp90 distribution in lung samples to determine their location and post-translational modifications. We found histological alterations that could be considered pathognomonic for COVID-19-related lung disease. Hsp60 and Hsp90 immunopositivity was significantly higher in the COVID-19 group compared to the controls, and immunolocalization was in the plasma membrane of the endothelial cells in COVID-19 subjects. The colocalization ratios for Hsp60/3-nitrotyrosine and Hsp60/acetylate-lisine were significantly increased in the COVID-19 group compared to the control group, similar to the colocalization ratio for Hsp90/acetylate-lisine. The histological and immunohistochemical findings led us to hypothesize that Hsp60 and Hsp90 might have a role in the onset of the thromboembolic phenomena that lead to death in a limited number of subjects affected by COVID-19. Further studies on a larger number of samples obtained from autopsies would allow to confirm these data as well as discover new biomarkers useful in the battle against this disease.

scholarly journals Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly

2020 ◽  
Vol 21 (23) ◽  
pp. 9186
Author(s):  
Rubén Hervás ◽  
Javier Oroz
Keyword(s):  
Molecular Chaperones ◽  
Protein Misfolding ◽  
Cell Damage ◽  
Protective Role ◽  
Soluble Proteins ◽  
Protein Deposits ◽  
Client Proteins ◽  
Recognition Motifs ◽  
Misfolding Diseases

Age-dependent alterations in the proteostasis network are crucial in the progress of prevalent neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, or amyotrophic lateral sclerosis, which are characterized by the presence of insoluble protein deposits in degenerating neurons. Because molecular chaperones deter misfolded protein aggregation, regulate functional phase separation, and even dissolve noxious aggregates, they are considered major sentinels impeding the molecular processes that lead to cell damage in the course of these diseases. Indeed, members of the chaperome, such as molecular chaperones and co-chaperones, are increasingly recognized as therapeutic targets for the development of treatments against degenerative proteinopathies. Chaperones must recognize diverse toxic clients of different orders (soluble proteins, biomolecular condensates, organized protein aggregates). It is therefore critical to understand the basis of the selective chaperone recognition to discern the mechanisms of action of chaperones in protein conformational diseases. This review aimed to define the selective interplay between chaperones and toxic client proteins and the basis for the protective role of these interactions. The presence and availability of chaperone recognition motifs in soluble proteins and in insoluble aggregates, both functional and pathogenic, are discussed. Finally, the formation of aberrant (pro-toxic) chaperone complexes will also be disclosed.

scholarly journals Hsp70 molecular chaperones: multifunctional allosteric holding and unfolding machines

2019 ◽  
Vol 476 (11) ◽  
pp. 1653-1677 ◽  
Author(s):  
Eugenia M. Clerico ◽  
Wenli Meng ◽  
Alexandra Pozhidaeva ◽  
Karishma Bhasne ◽  
Constantine Petridis ◽  
...  
Keyword(s):  
Molecular Chaperones ◽  
Protein Homeostasis ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
The Past ◽  
Hsp70 Family ◽  
Nucleotide Exchange Factors ◽  
Client Proteins ◽  
Structural Insights ◽  
Insight Into

AbstractThe Hsp70 family of chaperones works with its co-chaperones, the nucleotide exchange factors and J-domain proteins, to facilitate a multitude of cellular functions. Central players in protein homeostasis, these jacks-of-many-trades are utilized in a variety of ways because of their ability to bind with selective promiscuity to regions of their client proteins that are exposed when the client is unfolded, either fully or partially, or visits a conformational state that exposes the binding region in a regulated manner. The key to Hsp70 functions is that their substrate binding is transient and allosterically cycles in a nucleotide-dependent fashion between high- and low-affinity states. In the past few years, structural insights into the molecular mechanism of this allosterically regulated binding have emerged and provided deep insight into the deceptively simple Hsp70 molecular machine that is so widely harnessed by nature for diverse cellular functions. In this review, these structural insights are discussed to give a picture of the current understanding of how Hsp70 chaperones work.

scholarly journals HSP90 Molecular Chaperones, Metabolic Rewiring, and Epigenetics: Impact on Tumor Progression and Perspective for Anticancer Therapy

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 532 ◽  
Author(s):  
Valentina Condelli ◽  
Fabiana Crispo ◽  
Michele Pietrafesa ◽  
Giacomo Lettini ◽  
Danilo Swann Matassa ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Chaperones ◽  
Heat Shock Protein 90 ◽  
Anticancer Therapy ◽  
Cellular Functions ◽  
Master Regulators ◽  
Cellular Processes ◽  
Direct Binding ◽  
Client Proteins ◽  
The Relationship

Heat shock protein 90 (HSP90) molecular chaperones are a family of ubiquitous proteins participating in several cellular functions through the regulation of folding and/or assembly of large multiprotein complexes and client proteins. Thus, HSP90s chaperones are, directly or indirectly, master regulators of a variety of cellular processes, such as adaptation to stress, cell proliferation, motility, angiogenesis, and signal transduction. In recent years, it has been proposed that HSP90s play a crucial role in carcinogenesis as regulators of genotype-to-phenotype interplay. Indeed, HSP90 chaperones control metabolic rewiring, a hallmark of cancer cells, and influence the transcription of several of the key-genes responsible for tumorigenesis and cancer progression, through either direct binding to chromatin or through the quality control of transcription factors and epigenetic effectors. In this review, we will revise evidence suggesting how this interplay between epigenetics and metabolism may affect oncogenesis. We will examine the effect of metabolic rewiring on the accumulation of specific metabolites, and the changes in the availability of epigenetic co-factors and how this process can be controlled by HSP90 molecular chaperones. Understanding deeply the relationship between epigenetic and metabolism could disclose novel therapeutic scenarios that may lead to improvements in cancer treatment.

scholarly journals Molecular chaperones and stress-inducible protein-sorting factors coordinate the spatiotemporal distribution of protein aggregates

2012 ◽  
Vol 23 (16) ◽  
pp. 3041-3056 ◽  
Author(s):  
Liliana Malinovska ◽  
Sonja Kroschwald ◽  
Matthias C. Munder ◽  
Doris Richter ◽  
Simon Alberti
Keyword(s):  
Quality Control ◽  
Molecular Chaperones ◽  
Cellular Response ◽  
Protein Quality ◽  
Acute Stress ◽  
Protein Sorting ◽  
Protein Quality Control ◽  
Normal Growth ◽  
Small Heat Shock Protein ◽  
Misfolded Proteins

Acute stress causes a rapid redistribution of protein quality control components and aggregation-prone proteins to diverse subcellular compartments. How these remarkable changes come about is not well understood. Using a phenotypic reporter for a synthetic yeast prion, we identified two protein-sorting factors of the Hook family, termed Btn2 and Cur1, as key regulators of spatial protein quality control in Saccharomyces cerevisiae. Btn2 and Cur1 are undetectable under normal growth conditions but accumulate in stressed cells due to increased gene expression and reduced proteasomal turnover. Newly synthesized Btn2 can associate with the small heat shock protein Hsp42 to promote the sorting of misfolded proteins to a peripheral protein deposition site. Alternatively, Btn2 can bind to the chaperone Sis1 to facilitate the targeting of misfolded proteins to a juxtanuclear compartment. Protein redistribution by Btn2 is accompanied by a gradual depletion of Sis1 from the cytosol, which is mediated by the sorting factor Cur1. On the basis of these findings, we propose a dynamic model that explains the subcellular distribution of misfolded proteins as a function of the cytosolic concentrations of molecular chaperones and protein-sorting factors. Our model suggests that protein aggregation is not a haphazard process but rather an orchestrated cellular response that adjusts the flux of misfolded proteins to the capacities of the protein quality control system.

scholarly journals Structural and Functional Consequences Induced by Post-Translational Modifications in α-Defensins

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Enrico Balducci ◽  
Alessio Bonucci ◽  
Monica Picchianti ◽  
Rebecca Pogni ◽  
Eleonora Talluri
Keyword(s):  
Antimicrobial Peptide ◽  
Marked Change ◽  
Antibacterial Activities ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Adp Ribosylation ◽  
Functional Consequences ◽  
Adp Ribosyltransferase ◽  
Guanidino Group ◽  
Ribose Moiety

HNP-1 is an antimicrobial peptide that undergoes proteolytic cleavage to become a mature peptide. This process represents the mechanism commonly used by the cells to obtain a fully active antimicrobial peptide. In addition, it has been recently described that HNP-1 is recognized as substrate by the arginine-specific ADP-ribosyltransferase-1. Arginine-specific mono-ADP-ribosylation is an enzyme-catalyzed post-translational modification in which NAD+ serves as donor of the ADP-ribose moiety, which is transferred to the guanidino group of arginines in target proteins. While the arginine carries one positive charge, the ADP-ribose is negatively charged at the phosphate moieties at physiological pH. Therefore, the attachment of one or more ADP-ribose units results in a marked change of cationicity. ADP-ribosylation of HNP-1 drastically reduces its cytotoxic and antibacterial activities. While the chemotactic activity of HNP-1 remains unaltered, its ability to induce interleukin-8 production is enhanced. The arginine 14 of HNP-1 modified by the ADP-ribose is in some cases processed into ornithine, perhaps representing a different modality in the regulation of HNP-1 activities.

scholarly journals Post-Translational Modifications of FXR; Implications for Cholestasis and Obesity-Related Disorders

2021 ◽  
Vol 12 ◽  
Author(s):  
Monique D. Appelman ◽  
Suzanne W. van der Veen ◽  
Saskia W. C. van Mil
Keyword(s):  
Bile Acids ◽  
Posttranslational Modifications ◽  
Metabolic Disorders ◽  
Target Genes ◽  
Farnesoid X Receptor ◽  
Dietary Fats ◽  
Transcriptional Level ◽  
Alcoholic Fatty Liver ◽  
Post Translational Modifications ◽  
Functional Consequences

The Farnesoid X receptor (FXR) is a nuclear receptor which is activated by bile acids. Bile acids function in solubilization of dietary fats and vitamins in the intestine. In addition, bile acids have been increasingly recognized to act as signaling molecules involved in energy metabolism pathways, amongst others via activating FXR. Upon activation by bile acids, FXR controls the expression of many genes involved in bile acid, lipid, glucose and amino acid metabolism. An inability to properly use and store energy substrates may predispose to metabolic disorders, such as obesity, diabetes, cholestasis and non-alcoholic fatty liver disease. These diseases arise through a complex interplay between genetics, environment and nutrition. Due to its function in metabolism, FXR is an attractive treatment target for these disorders. The regulation of FXR expression and activity occurs both at the transcriptional and at the post-transcriptional level. It has been shown that FXR can be phosphorylated, SUMOylated and acetylated, amongst other modifications, and that these modifications have functional consequences for DNA and ligand binding, heterodimerization and subcellular localization of FXR. In addition, these post-translational modifications may selectively increase or decrease transcription of certain target genes. In this review, we provide an overview of the posttranslational modifications of FXR and discuss their potential involvement in cholestatic and metabolic disorders.

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