In this Review we describe recent advances that have increased our understanding of the molecular mechanisms and working principles of the Hsp70 network. This knowledge showcases how the Hsp70 chaperone system controls diverse cellular functions, and offers new opportunities for the development of chemical compounds that modulate disease-related Hsp70 activities.
The Hsp70 chaperone network. N2 - The kDa heat shock proteins Hsp70s are ubiquitous molecular chaperones that act in a large variety of cellular protein folding and remodelling processes. AB - The kDa heat shock proteins Hsp70s are ubiquitous molecular chaperones that act in a large variety of cellular protein folding and remodelling processes. Aust Regenerative Medicine Institute. Article 29 June Open Access. Hsp90 is required for the folding, stability and activity of several drivers of oncogenesis.
Here the authors show that Folliculin-interacting proteins FNIP 1 and 2, whose expression correlates with the cellular response to Hsp90 inhibitors, are co-chaperones of Hsp90 that function by inhibiting its ATPase activity. Eukaryotic ribosome biogenesis involves a large number of maturations factors which are responsible for the stepwise assembly of the ribosomal subunits. Here the authors use an array of biochemical and structural biology methods to investigate the function of the UtpA and UtpB complexes as part of the small subunit processome.
Article 27 June Open Access. Here the authors use high-resolution force spectroscopy to gain insight into the mechanism of action of an iron-tetrapyrrole with anti-prion properties. Article 25 April Open Access. Mutations in pendrin, a plasma membrane transporter, lead to Pendred syndrome, which is associated with hearing loss. Here, Jung et al. Article 06 April Open Access. Peter's Anomaly is a developmental disorder of the eye and has been linked to mutations in a range of genes, including the transcription factor FOXE3.
Oligomer-dependent and -independent chaperone activity of sHsps in different stressed conditions
Article 24 March Open Access. Molecular chaperones are recognized to interfere with protein aggregation, yet the underlying mechanisms are largely unknown. Here, the authors develop a kinetic model that reveals the variety of distinct microscopic mechanisms through which molecular chaperones act to suppress amyloid formation. Article 20 January Open Access.
Under stress conditions the molecular chaperone Hsp33 is activated to process unfolded proteins. Here, the authors use in vivo and in vitro crosslinking and 19 F-NMR to elucidate the binding site for misfolded proteins and are able to propose a model for its mechanism of action. Article 18 September Open Access. Hsp70 chaperones are essential for cellular proteostasis, and their function depends on allosteric communication between their nucleotide- and substrate-binding domains. Here, Kityk et al. Advanced search.
Skip to main content. Article 11 September Open Access The molecular basis of chaperone-mediated interleukin 23 assembly control It is unclear how unassembled secretory pathway proteins are discriminated from misfolded ones. Article 09 August Open Access HSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N 6 -methyladenosine Cells respond to heat shock with transcriptional and translational adaptations but how HSP90 inhibition alters the heat shock proteome is largely unclear.
Article 08 August Open Access Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor Hsp chaperones stabilize the inactive conformation of androgen receptor AR and are released upon hormone-induced AR activation.
Article 12 June Open Access Hsp90 middle domain phosphorylation initiates a complex conformational program to recruit the ATPase-stimulating cochaperone Aha1 Phosphorylation of Tyr in Hsp90 enhances the binding to its activator Aha1, but the underlying mechanism is unknown. Article 06 March Open Access Local unfolding of the HSP27 monomer regulates chaperone activity The small heat-shock protein HSP27 occurs predominantly in oligomeric forms, which makes its structural characterisation challenging.
Article 15 February Open Access Structural insights into chaperone addiction of toxin-antitoxin systems SecB homologs can be associated with stress-responsive type II toxin—antitoxin TA systems and form tripartite toxin-antitoxin-chaperone systems TAC. Article 01 November Open Access Competing protein-protein interactions regulate binding of Hsp27 to its client protein tau Small heat shock proteins sHSPs limit the aggregation of proteins, such as tau. Article 23 May Open Access Protein polarization driven by nucleoid exclusion of DnaK HSP70 —substrate complexes Many bacterial proteins exhibit spatially defined localization important for function.
Article 14 May Open Access Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N -acyl- N -alkyl sulfonamide Chemically modifying proteins is hard to achieve selectively without purifying the target protein. Article 16 April Open Access A switch point in the molecular chaperone Hsp90 responding to client interaction The heat shock protein 90 Hsp90 chaperone undergoes large conformational changes during its functional cycle.
Article 12 March Open Access TRiC controls transcription resumption after UV damage by regulating Cockayne syndrome protein A An integrated network of chaperones and protein degradation machineries called the proteostasis network PN is required to maintain protein homeostasis. Article 28 February Open Access Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis Aggregation is sequence-specific and nucleated by short aggregating protein segments APR.
Article 02 February Open Access UFD-2 is an adaptor-assisted E3 ligase targeting unfolded proteins The U-box ubiquitin ligase UFD-2 is one of the most abundant components of the ubiquitin proteasome system in muscle cells. Article 18 January Open Access A biosensor-based framework to measure latent proteostasis capacity A pool of quality control proteins QC maintains the protein-folding homeostasis in the cell, but its quantitative analysis is challenging.
Article 17 January Open Access Phosphorylation induced cochaperone unfolding promotes kinase recruitment and client class-specific Hsp90 phosphorylation The Hsp90 chaperone cycle is influenced by multiple phosphorylation events but their regulatory functions are poorly understood. Article 22 December Open Access Methylation-regulated decommissioning of multimeric PP2A complexes Protein phosphatase 2A PP2A forms different holoenzymes but little is known about the disassembly of these important signalling complexes.
Article 28 November Open Access The chromatin remodeling factor ISW-1 integrates organismal responses against nuclear and mitochondrial stress Changes in chromatin structure have been linked to organismal ageing. Article 31 October Open Access Conformation transitions of the polypeptide-binding pocket support an active substrate release from Hsp70s Hsp70s are highly conserved molecular chaperones that play multiple essential roles in maintaining cellular protein homeostasis.
Article 16 October Open Access The Hsp70 homolog Ssb affects ribosome biogenesis via the TORC1-Sch9 signaling pathway The yeast Hsp70 homolog Ssb is a chaperone that binds translating ribosomes where it is thought to function primarily by promoting nascent peptide folding.
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Article 22 September Open Access Trigger factor chaperone acts as a mechanical foldase Proteins fold under mechanical force during co-translational folding at the ribosome. Article 25 August Open Access HSPHrd1 axis precludes the oncorepressor potential of N-terminal misfolded Blimp-1s in lymphoma cells The transcriptional repressor Blimp-1 has an important role in B-cell differentiation. Article 30 June Open Access GroEL actively stimulates folding of the endogenous substrate protein PepQ In the prevailing model for assisted protein folding, chaperonins act passively by preventing protein aggregation.
Article 24 May Open Access An Hsp90 co-chaperone protein in yeast is functionally replaced by site-specific posttranslational modification in humans The eukaryotic heat shock protein 90 Hsp90 undergoes an ATP-dependent conformational cycle that is influenced by posttranslational modifications and co-chaperones. Article 02 February Open Access Molecular basis for protection of ribosomal protein L4 from cellular degradation Acl4 is a dedicated assembly chaperone for ribosomal protein RpL4 that recognizes RpL4 in the cytoplasm to facilitate its nuclear import.
Article 05 December Open Access Multivalent contacts of the Hsp70 Ssb contribute to its architecture on ribosomes and nascent chain interaction The correct folding of proteins often requires the intervention molecular chaperones, which can occur co-translationally. Article 30 November Open Access Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding Small heat shock proteins sHsps contribute to cellular recovery and survival following stress causing elevated levels of misfolded or unfolded proteins.
Article 24 November Open Access Interaction of the cotranslational Hsp70 Ssb with ribosomal proteins and rRNA depends on its lid domain In yeast, the heterodimeric ribosome-associated complex RAC acts in concert with the Hsp70 protein Ssb, forming a unique chaperone triad.
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Article 09 November Open Access Chaperone addiction of toxin—antitoxin systems Some bacterial toxin-antitoxin systems consist of a labile antitoxin that inhibits a toxin, and a chaperone that stabilizes the antitoxin. Article 06 October Open Access ARD1-mediated Hsp70 acetylation balances stress-induced protein refolding and degradation The chaperone Hsp70 has a dual role, promoting both protein refolding and protein degradation. Article 16 September Open Access Determining crystal structures through crowdsourcing and coursework Building crystal structures into the electron density is an important step in protein structure solution.
Article 29 June Open Access The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding Hsp90 is required for the folding, stability and activity of several drivers of oncogenesis. Article 29 June Open Access UtpA and UtpB chaperone nascent pre-ribosomal RNA and U3 snoRNA to initiate eukaryotic ribosome assembly Eukaryotic ribosome biogenesis involves a large number of maturations factors which are responsible for the stepwise assembly of the ribosomal subunits.
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Article 24 March Open Access Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation Molecular chaperones are recognized to interfere with protein aggregation, yet the underlying mechanisms are largely unknown. Article 20 January Open Access Protein unfolding as a switch from self-recognition to high-affinity client binding Under stress conditions the molecular chaperone Hsp33 is activated to process unfolded proteins. Article 18 September Open Access Pathways of allosteric regulation in Hsp70 chaperones Hsp70 chaperones are essential for cellular proteostasis, and their function depends on allosteric communication between their nucleotide- and substrate-binding domains.
Browse broader subjects Protein folding Proteins. The AutophagyDB aims to integrate a list of autophagy-related proteins and their potential orthologs in 41 eukaryotes and the THANATOS mainly contains proteins potentially associated with autophagy cell death pathways in eukaryotes. As to ncRDeathDB, it mainly provides noncoding RNA-associated cell death interactions and helps to visualize and navigate current knowledge of the noncoding RNA component of cell death and autophagy. For this database, it only contains autophagy related microRNAs.
And, ACDB only contains information of compounds with corresponding signaling pathways and potential targets in different diseases. In , Tamas Korcsmaros et al. It not only provides data on post-translational, transcriptional and post-transcriptional regulators, but also makes a connection between the cellular signaling network and the regulation of autophagy.
It focuses on the network analysis and helps the investigation of transcription factors, miRNAs and signaling pathways. Compared with ARN, HAMdb pays more attention to specific mechanism of autophagy modulators and related experimental information and study status. It covers not only structural and biological information, but also some functional information including specific effect on autophagy, pathway, disease, upstream, downstream and their corresponding reference.
Based on the information obtained from HAMdb, researchers can have an overall understanding of autophagy process and the related pathways. More important, it will help to uncover the relationship between autophagy and various diseases and thus promote the autophagy study in pharmacological and pathophysiological area. Autophagy, as an essential, conserved lysosomal degradation pathway that controls the quality of the cytoplasm by eliminating protein aggregates and damaged organelles, has been extensively studied in recent years.
Not only its basic cellular mechanism, but also its role in human health and disease has become widespread.
Considering the key role of autophagy in cell biology and its considerable therapeutic potential for various diseases, the comprehensive understanding of autophagy-related modulators and corresponding pathway and diseases information will be of great help for identifying new diagnostic and therapeutic targets. Inspired by the lack of autophagy-related pathway and disease information, we manually collected the literatures and integrated external resources to gain a high coverage autophagy database.
HAMdb contains proteins, chemicals and microRNAs from scientific literatures and cell lines. Their specific effect on autophagy, physicochemical information, biological information and disease information were carefully collected and compiled. Additionally, a lot of external links were available for more information including sequence database, 3D structure database, protein—protein interaction database, chemistry database and so on. The user-friendly website of HAMdb allows researchers without computational background to query, search and browse the database.
HAMdb will help researchers to understand the whole autophagy process and give detailed information about related diseases.
Furthermore, it can give hints for discovery of new modulators and identify new diagnostic and therapeutic targets. In the long run, HAMdb has the potential to promote the autophagy research in pharmacological and pathophysiological area. Cell Mol Life Sci 69 7 — Cell Res 24 1 — Nat Rev Clin Oncol 8 9 — Mizushima N, Komatsu M Autophagy: renovation of cells and tissues.