scholarly journals Redefining Molecular Chaperones as Chaotropes

2021 ◽  
Vol 8 ◽  
Author(s):  
Jakub Macošek ◽  
Guillaume Mas ◽  
Sebastian Hiller
Keyword(s):  
Molecular Chaperones ◽  
Protein Denaturation ◽  
Protein Homeostasis ◽  
Bacterial Protein ◽  
Client Protein ◽  
Dynamic Interactions ◽  
Biophysical Mechanism ◽  
Functional Regulation ◽  
Client Proteins

Molecular chaperones are the key instruments of bacterial protein homeostasis. Chaperones not only facilitate folding of client proteins, but also transport them, prevent their aggregation, dissolve aggregates and resolve misfolded states. Despite this seemingly large variety, single chaperones can perform several of these functions even on multiple different clients, thus suggesting a single biophysical mechanism underlying. Numerous recently elucidated structures of bacterial chaperone–client complexes show that dynamic interactions between chaperones and their client proteins stabilize conformationally flexible non-native client states, which results in client protein denaturation. Based on these findings, we propose chaotropicity as a suitable biophysical concept to rationalize the generic activity of chaperones. We discuss the consequences of applying this concept in the context of ATP-dependent and -independent chaperones and their functional regulation.

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 Hsp70 chaperone: a master player in protein homeostasis

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1497 ◽  
Author(s):  
María Rosario Fernández-Fernández ◽  
José María Valpuesta
Keyword(s):  
Structural Information ◽  
Protein Complexes ◽  
Protein Homeostasis ◽  
Client Protein ◽  
P Protein ◽  
Hsp70 Chaperone ◽  
Cellular Context ◽  
Client Proteins ◽  
Functional Mechanisms

Protein homeostasis (proteostasis) is an essential pillar for correct cellular function. Impairments in proteostasis are encountered both in aging and in several human disease conditions. Molecular chaperones are important players for proteostasis; in particular, heat shock protein 70 (Hsp70) has an essential role in protein folding, disaggregation, and degradation. We have recently proposed a model for Hsp70 functioning as a “multiple socket”. In the model, Hsp70 provides a physical platform for the binding of client proteins, other chaperones, and cochaperones. The final fate of the client protein is dictated by the set of Hsp70 interactions that occur in a given cellular context. Obtaining structural information of the different Hsp70-based protein complexes will provide valuable knowledge to understand the functional mechanisms behind the master role of Hsp70 in proteostasis. We additionally evaluate some of the challenges for attaining high-resolution structures of such complexes.

scholarly journals DNAJB chaperones inhibit aggregation of destabilised proteins via a C-terminal region distinct from that used to prevent amyloid formation

2020 ◽  
Author(s):  
Shannon McMahon ◽  
Steven Bergink ◽  
Harm H. Kampinga ◽  
Heath Ecroyd
Keyword(s):  
Protein Aggregation ◽  
Molecular Chaperones ◽  
Firefly Luciferase ◽  
Amyloid Formation ◽  
Protein Homeostasis ◽  
Formation Processes ◽  
Inclusion Formation ◽  
Different Types ◽  
Summary Statement ◽  
Client Proteins

AbstractDisturbances to protein homeostasis (proteostasis) can lead to protein aggregation and inclusion formation, processes associated with a variety of neurodegenerative disorders. DNAJBs are molecular chaperones previously identified as potent suppressors of disease-related protein aggregation. In this work, we over-expressed a destabilised isoform of firefly luciferase (R188Q/R261Q Fluc; FlucDM) in cells to assess the capacity of DNAJBs to inhibit inclusion formation. Co-expression of all DNAJBs tested significantly inhibited the intracellular aggregation of FlucDM. Moreover, we show that DNAJBs suppress aggregation by supporting the Hsp70-dependent degradation of FlucDM via the proteasome. The serine-rich stretch in DNAJB6 and DNAJB8, essential for preventing fibrillar aggregation, is not involved in the suppression of FlucDM inclusion formation. Conversely, deletion of the C-terminal TTK-LKS region in DNAJB8, a region not required to suppress polyQ aggregation, abolished its ability to inhibit inclusion formation by FlucDM. Thus, our data suggest that DNAJB6 and DNAJB8 possess two distinct domains involved in the inhibition of protein aggregation, one responsible for binding to β-hairpins that form during amyloid formation and another that mediates the degradation of destabilised client proteins via the proteasome.Summary statementSpecialised DNAJB molecular chaperones are potent suppressors of protein aggregation and interact with different types of client proteins via distinct C-terminal regions

scholarly journals PDI Family Members as Guides for Client Folding and Assembly

2020 ◽  
Vol 21 (24) ◽  
pp. 9351
Author(s):  
Shingo Kanemura ◽  
Motonori Matsusaki ◽  
Kenji Inaba ◽  
Masaki Okumura
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Viability ◽  
Molecular Chaperones ◽  
Protein Disulfide Isomerase ◽  
Family Members ◽  
Secretory Proteins ◽  
Efficient Production ◽  
Protein Homeostasis ◽  
Disulfide Isomerase ◽  
Protein Disulfide

Complicated and sophisticated protein homeostasis (proteostasis) networks in the endoplasmic reticulum (ER), comprising disulfide catalysts, molecular chaperones, and their regulators, help to maintain cell viability. Newly synthesized proteins inserted into the ER need to fold and assemble into unique native structures to fulfill their physiological functions, and this is assisted by protein disulfide isomerase (PDI) family. Herein, we focus on recent advances in understanding the detailed mechanisms of PDI family members as guides for client folding and assembly to ensure the efficient production of secretory proteins.

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 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 Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Xu Zheng ◽  
Joanna Krakowiak ◽  
Nikit Patel ◽  
Ali Beyzavi ◽  
Jideofor Ezike ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Heat Shock ◽  
Signaling Pathways ◽  
Molecular Chaperones ◽  
Stress Resistance ◽  
Dynamic Control ◽  
Protein Homeostasis ◽  
Unfolded Proteins ◽  
Cell Signaling Pathways ◽  
Chaperone Hsp70

Heat shock factor (Hsf1) regulates the expression of molecular chaperones to maintain protein homeostasis. Despite its central role in stress resistance, disease and aging, the mechanisms that control Hsf1 activity remain unresolved. Here we show that in budding yeast, Hsf1 basally associates with the chaperone Hsp70 and this association is transiently disrupted by heat shock, providing the first evidence that a chaperone repressor directly regulates Hsf1 activity. We develop and experimentally validate a mathematical model of Hsf1 activation by heat shock in which unfolded proteins compete with Hsf1 for binding to Hsp70. Surprisingly, we find that Hsf1 phosphorylation, previously thought to be required for activation, in fact only positively tunes Hsf1 and does so without affecting Hsp70 binding. Our work reveals two uncoupled forms of regulation - an ON/OFF chaperone switch and a tunable phosphorylation gain - that allow Hsf1 to flexibly integrate signals from the proteostasis network and cell signaling pathways.

An Overview of the Role of Molecular Chaperones in Protein Homeostasis

2011 ◽  
Vol 18 (2) ◽  
pp. 101-109 ◽  
Author(s):  
Ana O. Tiroli-Cepeda ◽  
Carlos H.I. Ramos
Keyword(s):  
Molecular Chaperones ◽  
Protein Homeostasis

scholarly journals Chaperoning the Mononegavirales: Current Knowledge and Future Directions

2018 ◽  
Author(s):  
Victor Latorre ◽  
Florian Mattenberger ◽  
Ron Geller
Keyword(s):  
Molecular Chaperones ◽  
Current Knowledge ◽  
Small Subset ◽  
Protein Homeostasis ◽  
Emerging Infections ◽  
Therapeutic Approaches ◽  
Future Directions ◽  
Antiviral Therapies ◽  
Cellular Machinery ◽  
Cellular Pathways

The order Mononegavirales harbors numerous viruses of significant relevance for human health, including both established and emerging infections. Currently, vaccines are only available for a small subset of these viruses and antiviral therapies remain limited. Being obligate cellular parasites, viruses must utilize the cellular machinery for their replication and spread. Therefore, targeting cellular pathways used by viruses can provide novel therapeutic approaches. One of the key challenges confronted by both hosts and viruses alike is the successful folding and maturation of proteins. In cells, this task is faced by cellular molecular chaperones, a group of conserved and abundant proteins that oversee protein folding and help maintain protein homeostasis. In this review, we summarize the current knowledge of how the mononegavirales interact with cellular chaperones, highlight key gaps in our knowledge, and discuss the potential of chaperone inhibitors as antivirals.

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