Molecular Chaperones — Cellular Machines for Protein Folding
TL;DR: The molecular chaperones as mentioned in this paper are linear polymers synthesized by ribosomes from activated amino acids, which have to adopt the unique three-dimensional structure required for its function in the cell.
Abstract: Proteins are linear polymers synthesized by ribosomes from activated amino acids. The product of this biosynthetic process is a polypeptide chain, which has to adopt the unique three-dimensional structure required for its function in the cell. In 1972, Christian Anfinsen was awarded the Nobel Prize for Chemistry for showing that this folding process is autonomous in that it does not require any additional factors or input of energy. Based on in vitro experiments with purified proteins, it was suggested that the correct three-dimensional structure can form spontaneously in vivo once the newly synthesized protein leaves the ribosome. Furthermore, proteins were assumed to maintain their native conformation until they were degraded by specific enzymes. In the last decade this view of cellular protein folding has changed considerably. It has become clear that a complicated and sophisticated machinery of proteins exists which assists protein folding and allows the functional state of proteins to be maintained under conditions in which they would normally unfold and aggregate. These proteins are collectively called molecular chaperones, because, like their human counterparts, they prevent unwanted interactions between their immature clients. In this review, we discuss the principal features of this peculiar class of proteins, their structure ± function relationships, and the underlying molecular mechanisms.
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TL;DR: This review focuses on how heart cells process ion channel proteins and how this protein trafficking may be altered in some cardiac arrhythmia diseases.
Abstract: The mechanisms underlying normal and abnormal cardiac rhythms are complex and incompletely understood Through the study of uncommon inheritable arrhythmia syndromes, including the long QT and Brugada syndromes, new insights are emerging At the cellular and tissue levels, we now recognize that ion channel current is the sum of biophysical (gating, permeation), biochemical (phosphorylation, etc), and biogenic (biosynthesis, processing, trafficking, and degradation) properties This review focuses on how heart cells process ion channel proteins and how this protein trafficking may be altered in some cardiac arrhythmia diseases In this review, we honor Dr Harry A Fozzard, a modern pioneer in cardiac arrhythmias, cell biology, and molecular electrophysiology As a scientist and physician, his writings and mentorship have served to foster a generation of investigators who continue to bring this complex field toward greater scientific understanding and impact on humankind
221 citations
TL;DR: In vitro analysis revealed that Hsp12, unlike all other Hsps studied so far, is completely unfolded; however, in the presence of certain lipids, it adopts a helical structure and does not alter the overall lipid composition of the plasma membrane but increases membrane stability.
153 citations
Cites background from "Molecular Chaperones — Cellular Mac..."
...Many of the conserved Hsps function as molecular chaperones in preventing or reversing the nonspecific aggregation of other proteins (Walter and Buchner, 2002)....
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TL;DR: The DnaK system in S. aureus plays a significant role in the survival of S.aureus under various stress conditions and resulted in a decrease in the ability of the organism to survive in a mouse host during a systemic infection.
Abstract: Heat-shock proteins are essential for stress tolerance and allowing organisms to survive conditions that cause protein unfolding. The role of the Staphylococcus aureus DnaK system in tolerance of various stresses was studied by disruption of dnaK by partial deletion and insertion of a kanamycin gene cassette. Deletion of dnaK in S. aureus strain COL resulted in poor growth at temperatures of 37 degrees C and above, and reduced carotenoid production. The mutant strain also exhibited increased susceptibility to oxidative and cell-wall-active antibiotic stress conditions. In addition, the mutant strain had slower rates of autolysis, suggesting a correlation between DnaK and functional expression of staphylococcal autolysins. Deletion of dnaK also resulted in a decrease in the ability of the organism to survive in a mouse host during a systemic infection. In summary, the DnaK system in S. aureus plays a significant role in the survival of S. aureus under various stress conditions.
121 citations
Cites background from "Molecular Chaperones — Cellular Mac..."
...The Hsps bind and release hydrophobic segments of an unfolded polypeptide chain in an ATP-hydrolytic reaction cycle (Hartl, 1996; Walter & Buchner, 2002)....
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...They prevent misfolding and aggregation of proteins, and promote their refolding and proper assembly under normal and stress conditions (Checa & Viale, 1997; Craig, 1985; Diamant & Goloubinoff, 1998; Hartl, 1996; Hubbard & Sander, 1991; Walter & Buchner, 2002)....
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TL;DR: A model that can explain the role of various classes of molecular chaperones and their co‐chaperones is described, and the possible involvement of chaperone in the propagation of mammalian prions is speculated on.
Abstract: Newly made polypeptide chains require the help of molecular chaperones not only to rapidly reach their final three-dimensional forms, but also to unfold and then correctly refold them back to their biologically active form should they misfold. Most prions are an unusual type of protein that can exist in one of two stable conformations, one of which leads to formation of an infectious alternatively folded form. Studies in Baker's yeast (Saccharomyces cerevisiae) have revealed that prions can exploit the molecular chaperone machinery in the cell in order to ensure stable propagation of the infectious, aggregation-prone form. The disaggregation of yeast prion aggregates by molecular chaperones generates forms of the prion protein that can seed the protein polymerisation that underlies the prion propagation cycle. In this article, we review what we have learnt about the role of molecular chaperones in yeast prion propagation, describe a model that can explain the role of various classes of molecular chaperones and their co-chaperones, and speculate on the possible involvement of chaperones in the propagation of mammalian prions.
105 citations
TL;DR: It is shown that temperature sensing by Hsp26 is a feature of its middle domain that changes its conformation within a narrow temperature range, and this structural rearrangement allows HSp26 to respond autonomously and directly to heat stress by reversibly unleashing its chaperone activity.
100 citations
Cites background from "Molecular Chaperones — Cellular Mac..."
...Most chaperones exploit ATP binding and hydrolysis to cycle between states with different affinities for their polypeptide substrates (Beissinger and Buchner, 1998; Bukau and Horwich, 1998; Hendrick and Hartl, 1993; Walter and Buchner, 2002)....
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...Commonly, ATP binding and hydrolysis are utilized to switch from a highto low-affinity state, which in turn releases the substrate from the chaperone and allows its refolding (Bukau and Horwich, 1998; Hartl, 1996; Walter and Buchner, 2002)....
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TL;DR: This review discusses the principal features of this peculiar class of proteins, their structure-function relationships, and the underlying molecular mechanisms that allow the functional state of proteins to be maintained under conditions in which they would normally unfold and aggregate.
Abstract: Proteins are linear polymers synthesized by ribosomes from activated amino acids. The product of this biosynthetic process is a polypeptide chain, which has to adopt the unique three-dimensional structure required for its function in the cell. In 1972, Christian Anfinsen was awarded the Nobel Prize for Chemistry for showing that this folding process is autonomous in that it does not require any additional factors or input of energy. Based on in vitro experiments with purified proteins, it was suggested that the correct three-dimensional structure can form spontaneously in vivo once the newly synthesized protein leaves the ribosome. Furthermore, proteins were assumed to maintain their native conformation until they were degraded by specific enzymes. In the last decade this view of cellular protein folding has changed considerably. It has become clear that a complicated and sophisticated machinery of proteins exists which assists protein folding and allows the functional state of proteins to be maintained under conditions in which they would normally unfold and aggregate. These proteins are collectively called molecular chaperones, because, like their human counterparts, they prevent unwanted interactions between their immature clients. In this review, we discuss the principal features of this peculiar class of proteins, their structure ± function relationships, and the underlying molecular mechanisms.
399 citations