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FEBS Letters Aug 2022Casein micelles are extracellular polydisperse assemblies of unstructured casein proteins. Caseins are the major component of milk. Within casein micelles, casein... (Review)
Review
Casein micelles are extracellular polydisperse assemblies of unstructured casein proteins. Caseins are the major component of milk. Within casein micelles, casein molecules are stabilised by binding to calcium phosphate nanoclusters and, by acting as molecular chaperones, through multivalent interactions. In the light of such interactions, we discuss whether casein micelles can be considered as extracellular condensates formed by liquid-liquid phase separation. We analyse the sequence, structure and interactions of caseins in comparison with proteins forming intracellular condensates. Furthermore, we review the similarities between caseins and small heat-shock proteins whose chaperone activity is linked to phase separation of proteins. By bringing these observations together, we describe a regulatory mechanism for protein condensates, as exemplified by casein micelles.
Topics: Animals; Caseins; Intrinsically Disordered Proteins; Micelles; Milk; Molecular Chaperones; Protein Folding
PubMed: 35815989
DOI: 10.1002/1873-3468.14449 -
Philosophical Transactions of the Royal... Jan 2018Maintenance of protein homeostasis is vitally important in post-mitotic cells, particularly neurons. Neurodegenerative diseases such as polyglutamine expansion... (Review)
Review
Maintenance of protein homeostasis is vitally important in post-mitotic cells, particularly neurons. Neurodegenerative diseases such as polyglutamine expansion disorders-like Huntington's disease or spinocerebellar ataxia (SCA), Alzheimer's disease, fronto-temporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease-are often characterized by the presence of inclusions of aggregated protein. Neurons contain complex protein networks dedicated to protein quality control and maintaining protein homeostasis, or proteostasis. Molecular chaperones are a class of proteins with prominent roles in maintaining proteostasis, which act to bind and shield hydrophobic regions of nascent or misfolded proteins while allowing correct folding, conformational changes and enabling quality control. There are many different families of molecular chaperones with multiple functions in proteostasis. The DNAJ family of molecular chaperones is the largest chaperone family and is defined by the J-domain, which regulates the function of HSP70 chaperones. DNAJ proteins can also have multiple other protein domains such as ubiquitin-interacting motifs or clathrin-binding domains leading to diverse and specific roles in the cell, including targeting client proteins for degradation via the proteasome, chaperone-mediated autophagy and uncoating clathrin-coated vesicles. DNAJ proteins can also contain ER-signal peptides or mitochondrial leader sequences, targeting them to specific organelles in the cell. In this review, we discuss the multiple roles of DNAJ proteins and in particular focus on the role of DNAJ proteins in protecting against neurodegenerative diseases caused by misfolded proteins. We also discuss the role of DNAJ proteins as direct causes of inherited neurodegeneration via mutations in family genes.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.
Topics: Animals; Fetal Proteins; HSP40 Heat-Shock Proteins; Humans; Mice; Molecular Chaperones; Neurodegenerative Diseases; Protein Folding; Rats
PubMed: 29203718
DOI: 10.1098/rstb.2016.0534 -
Protein Science : a Publication of the... Jul 2017Protein folding is well known to be supervised by a dedicated class of proteins called chaperones. However, the core mode of action of these molecular machines has... (Review)
Review
Protein folding is well known to be supervised by a dedicated class of proteins called chaperones. However, the core mode of action of these molecular machines has remained elusive due to several reasons including the promiscuous nature of the interactions between chaperones and their many clients, as well as the dynamics and heterogeneity of chaperone conformations and the folding process itself. While troublesome for traditional bulk techniques, these properties make an excellent case for the use of single-molecule approaches. In this review, we will discuss how force spectroscopy, fluorescence microscopy, FCS, and FRET methods are starting to zoom in on this intriguing and diverse molecular toolbox that is of direct importance for protein quality control in cells, as well as numerous degenerative conditions that depend on it.
Topics: Animals; Fluorescence Resonance Energy Transfer; Humans; Microscopy, Fluorescence; Molecular Chaperones; Protein Folding
PubMed: 28342267
DOI: 10.1002/pro.3161 -
Haematologica Jun 2021Erythropoiesis is a tightly regulated cell differentiation process in which specialized oxygen- and carbon dioxide-carrying red blood cells are generated in vertebrates.... (Review)
Review
Erythropoiesis is a tightly regulated cell differentiation process in which specialized oxygen- and carbon dioxide-carrying red blood cells are generated in vertebrates. Extensive reorganization and depletion of the erythroblast proteome leading to the deterioration of general cellular protein quality control pathways and rapid hemoglobin biogenesis rates could generate misfolded/aggregated proteins and trigger proteotoxic stresses during erythropoiesis. Such cytotoxic conditions could prevent proper cell differentiation resulting in premature apoptosis of erythroblasts (ineffective erythropoiesis). The heat shock protein 70 (Hsp70) molecular chaperone system supports a plethora of functions that help maintain cellular protein homeostasis (proteostasis) and promote red blood cell differentiation and survival. Recent findings show that abnormalities in the expression, localization and function of the members of this chaperone system are linked to ineffective erythropoiesis in multiple hematological diseases in humans. In this review, we present latest advances in our understanding of the distinct functions of this chaperone system in differentiating erythroblasts and terminally differentiated mature erythrocytes. We present new insights into the protein repair-only function(s) of the Hsp70 system, perhaps to minimize protein degradation in mature erythrocytes to warrant their optimal function and survival in the vasculature under healthy conditions. The work also discusses the modulatory roles of this chaperone system in a wide range of hematological diseases and the therapeutic gain of targeting Hsp70.
Topics: Animals; Erythroblasts; Erythrocytes; Erythropoiesis; HSP70 Heat-Shock Proteins; Humans; Molecular Chaperones
PubMed: 33832207
DOI: 10.3324/haematol.2019.233056 -
Journal of Molecular Biology Sep 2015Protein homeostasis (proteostasis) is inextricably tied to cellular health and organismal lifespan. Aging, exposure to physiological and environmental stress, and... (Review)
Review
Protein homeostasis (proteostasis) is inextricably tied to cellular health and organismal lifespan. Aging, exposure to physiological and environmental stress, and expression of mutant and metastable proteins can cause an imbalance in the protein-folding landscape, which results in the formation of non-native protein aggregates that challenge the capacity of the proteostasis network (PN), increasing the risk for diseases associated with misfolding, aggregation, and aberrant regulation of cell stress responses. Molecular chaperones have central roles in each of the arms of the PN (protein synthesis, folding, disaggregation, and degradation), leading to the proposal that modulation of chaperone function could have therapeutic benefits for the large and growing family of diseases of protein conformation including neurodegeneration, metabolic diseases, and cancer. In this review, we will discuss the current strategies used to tune the PN through targeting molecular chaperones and assess the potential of the chemical biology of proteostasis.
Topics: Aging; Heat-Shock Response; Humans; Molecular Chaperones; Protein Aggregates; Protein Conformation; Protein Folding; Stress, Physiological
PubMed: 26003923
DOI: 10.1016/j.jmb.2015.05.010 -
International Journal of Molecular... Oct 2019Most molecular chaperones belonging to heat shock protein (HSP) families are known to protect cancer cells from pathologic, environmental and pharmacological stress... (Review)
Review
Most molecular chaperones belonging to heat shock protein (HSP) families are known to protect cancer cells from pathologic, environmental and pharmacological stress factors and thereby can hamper anti-cancer therapies. In this review, we present data on inhibitors of the heat shock response (particularly mediated by the chaperones HSP90, HSP70, and HSP27) either as a single treatment or in combination with currently available anti-cancer therapeutic approaches. An overview of the current literature reveals that the co-administration of chaperone inhibitors and targeting drugs results in proteotoxic stress and violates the tumor cell physiology. An optimal drug combination should simultaneously target cytoprotective mechanisms and trigger the imbalance of the tumor cell physiology.
Topics: Antineoplastic Agents; Drug Therapy, Combination; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Isoxazoles; Molecular Chaperones; Neoplasms; Oligonucleotides; Resorcinols
PubMed: 31652993
DOI: 10.3390/ijms20215284 -
Non-cell Autonomous Maintenance of Proteostasis by Molecular Chaperones and Its Molecular Mechanism.Biological & Pharmaceutical Bulletin 2018Molecular chaperones have essential roles in cell survival, to prevent misfolding, aggregation, and aberrant accumulation of cellular proteins, and thus to maintain... (Review)
Review
Molecular chaperones have essential roles in cell survival, to prevent misfolding, aggregation, and aberrant accumulation of cellular proteins, and thus to maintain protein homeostasis (proteostasis). However, recent studies using animal models suggest that transcriptional upregulation of molecular chaperones in response to various types of stresses does not ubiquitously occur in all cells and tissues, but is a cell type-specific event. The imbalanced response to stresses between cells and tissues has been pointed out since more than 30 years ago, but the molecular basis as to how organisms maintain proteostasis in all cells, especially cells deficient for chaperone induction, remains unknown. In this review, I introduce the non-cell autonomous function of molecular chaperones that has been suggested in animal studies, especially focusing on our recent findings, and discuss the possibility that the non-cell autonomous function might provide a potential explanation as to how organisms would maintain proteostasis despite the imbalanced stress response between cells and tissues. Further elucidation of the molecular basis underlying the non-cell autonomous function of molecular chaperones would provide not only better understanding as to how organisms maintain proteostasis but also important insights into the potential development of therapies and diagnostics for the currently intractable neurodegenerative diseases that are associated with protein misfolding and aggregation.
Topics: Animals; Exosomes; Heat-Shock Proteins; Humans; Molecular Chaperones; Proteostasis
PubMed: 29863073
DOI: 10.1248/bpb.b18-00141 -
Philosophical Transactions of the Royal... Jan 2018The molecular chaperone heat shock protein 90 (Hsp90) facilitates metastable protein maturation, stabilization of aggregation-prone proteins, quality control of... (Review)
Review
The molecular chaperone heat shock protein 90 (Hsp90) facilitates metastable protein maturation, stabilization of aggregation-prone proteins, quality control of misfolded proteins and assists in keeping proteins in activation-competent conformations. Proteins that rely on Hsp90 for function are delivered to Hsp90 utilizing a co-chaperone-assisted cycle. Co-chaperones play a role in client transfer to Hsp90, Hsp90 ATPase regulation and stabilization of various Hsp90 conformational states. Many of the proteins chaperoned by Hsp90 (Hsp90 clients) are essential for the progression of various diseases, including cancer, Alzheimer's disease and other neurodegenerative diseases, as well as viral and bacterial infections. Given the importance of these clients in different diseases and their dynamic interplay with the chaperone machinery, it has been suggested that targeting Hsp90 and its respective co-chaperones may be an effective method for combating a large range of illnesses.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.
Topics: Animals; HSP90 Heat-Shock Proteins; Humans; Mammals
PubMed: 29203712
DOI: 10.1098/rstb.2016.0527 -
Traffic (Copenhagen, Denmark) Apr 2016Helenius and colleagues proposed over 20-years ago a paradigm-shifting model for how chaperone binding in the endoplasmic reticulum was mediated and controlled for a new... (Review)
Review
Helenius and colleagues proposed over 20-years ago a paradigm-shifting model for how chaperone binding in the endoplasmic reticulum was mediated and controlled for a new type of molecular chaperone- the carbohydrate-binding chaperones, calnexin and calreticulin. While the originally established basics for this lectin chaperone binding cycle holds true today, there has been a number of important advances that have expanded our understanding of its mechanisms of action, role in protein homeostasis, and its connection to disease states that are highlighted in this review.
Topics: Animals; Calnexin; Endoplasmic Reticulum; Humans; Molecular Chaperones; Polysaccharides; Protein Binding; Unfolded Protein Response
PubMed: 26676362
DOI: 10.1111/tra.12358 -
Biochimica Et Biophysica Acta Aug 2014Nascent polypeptides emerging from the ribosome are assisted by a pool of molecular chaperones and targeting factors, which enable them to efficiently partition as... (Review)
Review
Nascent polypeptides emerging from the ribosome are assisted by a pool of molecular chaperones and targeting factors, which enable them to efficiently partition as cytosolic, integral membrane or exported proteins. Extensive genetic and biochemical analyses have significantly expanded our knowledge of chaperone tasking throughout this process. In bacteria, it is known that the folding of newly-synthesized cytosolic proteins is mainly orchestrated by three highly conserved molecular chaperones, namely Trigger Factor (TF), DnaK (HSP70) and GroEL (HSP60). Yet, it has been reported that these major chaperones are strongly involved in protein translocation pathways as well. This review describes such essential molecular chaperone functions, with emphasis on both the biogenesis of inner membrane proteins and the post-translational targeting of presecretory proteins to the Sec and the twin-arginine translocation (Tat) pathways. Critical interplay between TF, DnaK, GroEL and other molecular chaperones and targeting factors, including SecB, SecA, the signal recognition particle (SRP) and the redox enzyme maturation proteins (REMPs) is also discussed. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey.
Topics: Bacteria; Cell Membrane; Chaperonin 60; HSP70 Heat-Shock Proteins; Molecular Chaperones; Oxidation-Reduction; Protein Transport; Signal Recognition Particle
PubMed: 24269840
DOI: 10.1016/j.bbamcr.2013.11.007