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Genes To Cells : Devoted To Molecular &... Jul 2001The AAA+ superfamily of ATPases, which contain a homologous ATPase module, are found in all kingdoms of living organisms where they participate in diverse cellular... (Review)
Review
The AAA+ superfamily of ATPases, which contain a homologous ATPase module, are found in all kingdoms of living organisms where they participate in diverse cellular processes including membrane fusion, proteolysis and DNA replication. Recent structural studies have revealed that they usually form ring-shaped oligomers, which are crucial for their ATPase activities and mechanisms of action. These ring-shaped oligomeric complexes are versatile in their mode of action, which collectively seem to involve some form of disruption of molecular or macromolecular structure; unfolding of proteins, disassembly of protein complexes, unwinding of DNA, or alteration of the state of DNA-protein complexes. Thus, the AAA+ proteins represent a novel type of molecular chaperone. Comparative analyses have also revealed significant similarities and differences in structure and molecular mechanism between AAA+ ATPases and other ring-shaped ATPases.
Topics: Adenosine Triphosphatases; Amino Acid Sequence; Animals; Conserved Sequence; DNA Replication; Eukaryotic Cells; Humans; Membrane Fusion; Molecular Chaperones; Mutation; Protein Structure, Tertiary
PubMed: 11473577
DOI: 10.1046/j.1365-2443.2001.00447.x -
Cellular and Molecular Life Sciences :... May 2009The endoplasmic reticulum (ER) is involved in a variety of essential and interconnected processes in human cells, including protein biogenesis, signal transduction, and... (Review)
Review
The endoplasmic reticulum (ER) is involved in a variety of essential and interconnected processes in human cells, including protein biogenesis, signal transduction, and calcium homeostasis. The central player in all these processes is the ER-lumenal polypeptide chain binding protein BiP that acts as a molecular chaperone. BiP belongs to the heat shock protein 70 (Hsp70) family and crucially depends on a number of interaction partners, including co-chaperones, nucleotide exchange factors, and signaling molecules. In the course of the last five years, several diseases have been linked to BiP and its interaction partners, such as a group of infectious diseases that are caused by Shigella toxin producing E. coli. Furthermore, the inherited diseases Marinesco-Sjögren syndrome, autosomal dominant polycystic liver disease, Wolcott-Rallison syndrome, and several cancer types can be considered BiP-related diseases. This review summarizes the physiological and pathophysiological characteristics of BiP and its interaction partners.
Topics: Calcium; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Escherichia coli Infections; Heat-Shock Proteins; Homeostasis; Humans; Liver Diseases; Models, Biological; Molecular Chaperones; Neoplasms; Protein Folding; Protein Transport; Signal Transduction; Spinocerebellar Degenerations; Syndrome
PubMed: 19151922
DOI: 10.1007/s00018-009-8745-y -
Biochimica Et Biophysica Acta Mar 2012Hsp90 is a dimeric molecular chaperone required for the activation and stabilization of numerous client proteins many of which are involved in essential cellular... (Review)
Review
Hsp90 is a dimeric molecular chaperone required for the activation and stabilization of numerous client proteins many of which are involved in essential cellular processes like signal transduction pathways. This activation process is regulated by ATP-induced large conformational changes, co-chaperones and posttranslational modifications. For some co-chaperones, a detailed picture on their structures and functions exists, for others their contributions to the Hsp90 system is still unclear. Recent progress on the conformational dynamics of Hsp90 and how co-chaperones affect the Hsp90 chaperone cycle significantly increased our understanding of the gearings of this complex molecular machinery. This article is part of a Special Issue entitled: Heat Shock Protein 90 (Hsp90).
Topics: Adenosine Triphosphate; Animals; Binding Sites; HSP90 Heat-Shock Proteins; Humans; Models, Molecular; Molecular Chaperones; Protein Binding; Protein Conformation
PubMed: 21951723
DOI: 10.1016/j.bbamcr.2011.09.003 -
The Journal of Biological Chemistry Oct 2015Many proteins can form amyloid-like fibrils in vitro, but only about 30 amyloids are linked to disease, whereas some proteins form physiological amyloid-like assemblies.... (Review)
Review
Many proteins can form amyloid-like fibrils in vitro, but only about 30 amyloids are linked to disease, whereas some proteins form physiological amyloid-like assemblies. This raises questions of how the formation of toxic protein species during amyloidogenesis is prevented or contained in vivo. Intrinsic chaperoning or regulatory factors can control the aggregation in different protein systems, thereby preventing unwanted aggregation and enabling the biological use of amyloidogenic proteins. The molecular actions of these chaperones and regulators provide clues to the prevention of amyloid disease, as well as to the harnessing of amyloidogenic proteins in medicine and biotechnology.
Topics: Amyloid; Animals; Humans; Molecular Chaperones
PubMed: 26354437
DOI: 10.1074/jbc.R115.653097 -
International Journal of Molecular... Dec 2019Thirty years ago a class of proteins was found to prevent the aggregation of Rubisco. These proteins' ability to prevent unwanted associations led to their being called... (Review)
Review
Thirty years ago a class of proteins was found to prevent the aggregation of Rubisco. These proteins' ability to prevent unwanted associations led to their being called chaperones. These chaperone proteins also increased in expression as a response to heat shock, hence their label as heat shock proteins (Hsps). However, neither label encompasses the breadth of these proteins' functional capabilities. The term "unfoldases" has been proposed, as this basic function is shared by most members of this protein family. Onto this is added specializations that allow the different family members to perform various cellular functions. This current article focuses on the resolved structural bases for these functions. It reviews the currently available molecular structures in the Protein Data Bank for several classes of Hsps (Hsp60, Hsp70, Hsp90, and Hsp104). When possible, it discusses the complete structures for these proteins, and the types of molecular machines to which they have been assigned. The structures of domains and the associated functions are discussed in order to illustrate the rationale for the proposed unfoldase function.
Topics: Bacteria; Databases, Protein; Eukaryota; History, 20th Century; History, 21st Century; Humans; Molecular Chaperones; Protein Conformation
PubMed: 31817979
DOI: 10.3390/ijms20246195 -
Biochimica Et Biophysica Acta.... Jun 2024Among the six known iron‑sulfur (FeS) cluster biogenesis machineries that function across all domains of life only one involves a molecular chaperone system. This... (Review)
Review
Among the six known iron‑sulfur (FeS) cluster biogenesis machineries that function across all domains of life only one involves a molecular chaperone system. This machinery, called ISC for 'iron sulfur cluster', functions in bacteria and in mitochondria of eukaryotes including humans. The chaperone system - a dedicated J-domain protein co-chaperone termed Hsc20 and its Hsp70 partner - is essential for proper ISC machinery function, interacting with the scaffold protein IscU which serves as a platform for cluster assembly and subsequent transfer onto recipient apo-proteins. Despite many years of research, surprisingly little is known about the specific role(s) that the chaperones play in the ISC machinery. Here we review three non-exclusive scenarios that range from involvement of the chaperones in the cluster transfer to regulation of the cellular levels of IscU itself.
Topics: Iron-Sulfur Proteins; Humans; Molecular Chaperones; HSP70 Heat-Shock Proteins; Mitochondria; Escherichia coli Proteins
PubMed: 38574821
DOI: 10.1016/j.bbamcr.2024.119717 -
Cell Stress & Chaperones Feb 2024The activity of the Hsp70 molecular chaperone is regulated by a suite of helper co-chaperones that include J-proteins. Studies on J-proteins have historically focused on... (Review)
Review
The activity of the Hsp70 molecular chaperone is regulated by a suite of helper co-chaperones that include J-proteins. Studies on J-proteins have historically focused on their expression, localization, and activation of Hsp70. There is growing evidence that the post-translational modifications (PTMs) of chaperones (the chaperone code) fine-tune chaperone function. This mini-review summarizes the current understanding of the role and regulation of PTMs on the major J-proteins Ydj1 and DNAJA1. Understanding these PTMs may provide novel therapeutic avenues for targeting chaperone activity in cancer and neurodegenerative diseases.
Topics: Molecular Chaperones; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Protein Folding; Protein Processing, Post-Translational
PubMed: 38309209
DOI: 10.1016/j.cstres.2023.11.001 -
Cell Structure and Function Oct 1996
Review
Topics: Animals; Collagen; Gene Expression Regulation; Heat-Shock Proteins; Liver Cirrhosis; Molecular Chaperones; Procollagen
PubMed: 9118251
DOI: 10.1247/csf.21.425 -
International Journal of Molecular... Nov 2022Heat shock proteins (HSPs) are highly conserved molecular chaperones with diverse cellular activities, including protein folding, assembly or disassembly of protein... (Review)
Review
Heat shock proteins (HSPs) are highly conserved molecular chaperones with diverse cellular activities, including protein folding, assembly or disassembly of protein complexes, and maturation process under diverse stress conditions. HSPs also play essential roles in tumorigenesis, metastasis, and therapeutic resistance across cancers. Among them, HSP40s are widely accepted as regulators of HSP70/HSP90 chaperones and an accumulating number of biological functions as molecular chaperones dependent or independent of either of these chaperones. Despite large numbers of HSP40s, little is known about their physiologic roles, specifically in cancer progression. This article summarizes the multi-faceted role of DNAJB proteins as one subclass of the HSP40 family in cancer development and metastasis. Regulation and deregulation of DNAJB proteins at transcriptional, post-transcriptional, and post-translational levels contribute to tumor progression, particularly cancer metastasis. Furthermore, understanding differences in function and regulating mechanism between DNAJB proteins offers a new perspective on tumorigenesis and metastasis to improve therapeutic opportunities for malignant diseases.
Topics: Humans; HSP40 Heat-Shock Proteins; Molecular Chaperones; Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Protein Folding; HSP90 Heat-Shock Proteins; Neoplasms
PubMed: 36499297
DOI: 10.3390/ijms232314970 -
Accounts of Chemical Research Mar 2018Molecular chaperone proteins perform a diversity of roles inside and outside the cell. One of the most important is the stabilization of misfolding proteins to prevent... (Review)
Review
Molecular chaperone proteins perform a diversity of roles inside and outside the cell. One of the most important is the stabilization of misfolding proteins to prevent their aggregation, a process that is potentially detrimental to cell viability. Diseases such as Alzheimer's, Parkinson's, and cataract are characterized by the accumulation of protein aggregates. In vivo, many proteins are metastable and therefore under mild destabilizing conditions have an inherent tendency to misfold, aggregate, and hence lose functionality. As a result, protein levels are tightly regulated inside and outside the cell. Protein homeostasis, or proteostasis, describes the network of biological pathways that ensures the proteome remains folded and functional. Proteostasis is a major factor in maintaining cell, tissue, and organismal viability. We have extensively investigated the structure and function of intra- and extracellular molecular chaperones that operate in an ATP-independent manner to stabilize proteins and prevent their misfolding and subsequent aggregation into amorphous particles or highly ordered amyloid fibrils. These types of chaperones are therefore crucial in maintaining proteostasis under normal and stress (e.g., elevated temperature) conditions. Despite their lack of sequence similarity, they exhibit many common features, i.e., extensive structural disorder, dynamism, malleability, heterogeneity, oligomerization, and similar mechanisms of chaperone action. In this Account, we concentrate on the chaperone roles of α-crystallins and caseins, the predominant proteins in the eye lens and milk, respectively. Intracellularly, the principal ATP-independent chaperones are the small heat-shock proteins (sHsps). In vivo, sHsps are the first line of defense in preventing intracellular protein aggregation. The lens proteins αA- and αB-crystallin are sHsps. They play a crucial role in maintaining solubility of the crystallins (including themselves) with age and hence in lens proteostasis and, ultimately, lens transparency. As there is little metabolic activity and no protein turnover in the lens, crystallins are very long lived proteins. Lens proteostasis is therefore very different to that in normal, metabolically active cells. Crystallins undergo extensive post-translational modification (PTM), including deamidation, racemization, phosphorylation, and truncation, which can alter their stability. Despite this, the lens remains transparent for tens of years, implying that lens proteostasis is intimately integrated with crystallin PTMs. Many PTMs do not significantly alter crystallin stability, solubility, and functionality, which thereby facilitates lens transparency. In the long term, however, extensive accumulation of crystallin PTMs leads to large-scale crystallin aggregation, lens opacification, and cataract formation. Extracellularly, various ATP-independent molecular chaperones exist that exhibit sHsp-like structural and functional features. For example, caseins, the major milk proteins, exhibit chaperone ability by inhibiting the amorphous and amyloid fibrillar aggregation of a diversity of destabilized proteins. Caseins maintain proteostasis within milk by preventing deleterious casein amyloid fibril formation via incorporation of thousands of individual caseins into an amorphous structure known as the casein micelle. Hundreds of nanoclusters of calcium phosphate are sequestered within each casein micelle through interactions with short, highly phosphorylated casein sequences. This results in a stable biofluid that contains a high concentration of potentially amyloidogenic caseins and concentrations of calcium and phosphate that can be far in excess of the solubility of calcium phosphate. Casein micelle formation therefore performs vital roles in neonatal nutrition and calcium homeostasis in the mammary gland.
Topics: Adenosine Triphosphate; Animals; Caseins; Humans; Lens, Crystalline; Milk; Molecular Chaperones; Protein Aggregates; Proteostasis; alpha-Crystallins
PubMed: 29442498
DOI: 10.1021/acs.accounts.7b00250