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1.
Heat-shock protein 90, a chaperone for folding and regulation 总被引:21,自引:0,他引:21
Picard D 《Cellular and molecular life sciences : CMLS》2002,59(10):1640-1648
Heat-shock protein 90 (Hsp90) is an abundant and highly conserved molecular chaperone that is essential for viability in
eukaryotes. Hsp90 fulfills a housekeeping function in contributing to the folding, maintenance of structural integrity and
proper regulation of a subset of cytosolic proteins. A remarkable proportion of its substrates are proteins involved in cell
cycle control and signal transduction. Hsp90 acts with a cohort of Hsp90 co-chaperones that modulate its substrate recognition,
ATPase cycle and chaperone function. The large conformational flexibility of Hsp90 and a multitude of dynamic co-chaperone
complexes contribute to generating functional diversity, and allow Hsp90 to assist a wide range of substrates. 相似文献
2.
Walter S 《Cellular and molecular life sciences : CMLS》2002,59(10):1589-1597
The Escherichia coli proteins GroEL and GroES were the first chaperones to be studied in detail and have thus become a role model for assisted protein folding in general. A wealth of both structural and functional data on the GroE system has been accumulated over the past years, enabling us now to understand the basic principles of how this fascinating protein-folding machine accomplishes its task. According to the current model, GroE processes a nonnative polypeptide in a cycle consisting of three steps. First, the polypeptide substrate is captured by GroEL. Upon binding of the co-chaperone GroES and ATP, the substrate is then discharged into a unique microenvironment inside of the chaperone, which promotes productive folding. After hydrolysis of ATP, the polypeptide is released into solution. Moreover, GroE may actively increase the folding efficiency, e.g. by unfolding of misfolded protein molecules. The mechanisms underlying these features, however, are yet not well characterized. 相似文献
3.
DnaJ/Hsp40 (heat shock protein 40) proteins have been preserved throughout evolution and are important for protein translation,
folding, unfolding, translocation, and degradation, primarily by stimulating the ATPase activity of chaperone proteins, Hsp70s.
Because the ATP hydrolysis is essential for the activity of Hsp70s, DnaJ/Hsp40 proteins actually determine the activity of
Hsp70s by stabilizing their interaction with substrate proteins. DnaJ/Hsp40 proteins all contain the J domain through which
they bind to Hsp70s and can be categorized into three groups, depending on the presence of other domains. Six DnaJ homologs
have been identified in Escherichia coli and 22 in Saccharomyces cerevisiae. Genome-wide analysis has revealed 41 DnaJ/Hsp40 family members (or putative members) in humans. While 34 contain the typical
J domains, 7 bear partially conserved J-like domains, but are still suggested to function as DnaJ/ Hsp40 proteins. DnaJA2b,
DnaJB1b, DnaJC2, DnaJC20, and DnaJC21 are named for the first time in this review; all other human DnaJ proteins were dubbed
according to their gene names, e.g. DnaJA1 is the human protein named after its gene DNAJA1. This review highlights the progress
in studying the domains in DnaJ/Hsp40 proteins, introduces the mechanisms by which they interact with Hsp70s, and stresses
their functional diversity.
Received 27 April 2006; received after revision 5 June 2006; accepted 19 July 2006 相似文献
4.
Protein folding and degradation in bacteria: to degrade or not to degrade? That is the question 总被引:11,自引:0,他引:11
In Escherichia coli protein quality control is carried out by a protein network, comprising chaperones and proteases. Central to this network
are two protein families, the AAA+ and the Hsp70 family. The major Hsp70 chaperone, DnaK, efficiently prevents protein aggregation
and supports the refolding of damaged proteins. In a special case, DnaK, together with the assistance of the AAA+ protein
ClpB, can also refold aggregated proteins. Other Hsp70 systems have more specialized functions in the cell, for instance HscA
appears to be involved in the assembly of Fe/S proteins. In contrast to ClpB, many AAA+ proteins associate with a peptidase
to form proteolytic machines which remove irreversibly damaged proteins from the cellular pool. The AAA+ component of these
proteolytic machines drives protein degradation. They are required not only for recognition of the substrate but also for
substrate unfolding and translocation into the proteolytic chamber. In many cases, specific adaptor proteins modify the substrate
binding properties of AAA+ proteins. While chaperones and proteases do not appear to directly cooperate with each other, both
systems appear to be necessary for proper functioning of the cell and can, at least in part, substitute for one another.
RID="*"
ID="*"Corresponding author. 相似文献
5.
Rayees U. H. Mattoo Pierre Goloubinoff 《Cellular and molecular life sciences : CMLS》2014,71(17):3311-3325
By virtue of their general ability to bind (hold) translocating or unfolding polypeptides otherwise doomed to aggregate, molecular chaperones are commonly dubbed “holdases”. Yet, chaperones also carry physiological functions that do not necessitate prevention of aggregation, such as altering the native states of proteins, as in the disassembly of SNARE complexes and clathrin coats. To carry such physiological functions, major members of the Hsp70, Hsp110, Hsp100, and Hsp60/CCT chaperone families act as catalytic unfolding enzymes or unfoldases that drive iterative cycles of protein binding, unfolding/pulling, and release. One unfoldase chaperone may thus successively convert many misfolded or alternatively folded polypeptide substrates into transiently unfolded intermediates, which, once released, can spontaneously refold into low-affinity native products. Whereas during stress, a large excess of non-catalytic chaperones in holding mode may optimally prevent protein aggregation, after the stress, catalytic disaggregases and unfoldases may act as nanomachines that use the energy of ATP hydrolysis to repair proteins with compromised conformations. Thus, holding and catalytic unfolding chaperones can act as primary cellular defenses against the formation of early misfolded and aggregated proteotoxic conformers in order to avert or retard the onset of degenerative protein conformational diseases. 相似文献
6.
sHsps and their role in the chaperone network 总被引:17,自引:0,他引:17
Haslbeck M 《Cellular and molecular life sciences : CMLS》2002,59(10):1649-1657
Small Hsps (sHsps) encompass a widespread but diverse class of proteins. These low molecular mass proteins (15—42 kDa) form
dynamic oligomeric structures ranging from 9 to 50 subunits. sHsps display chaperone function in vitro, and in addition they
have been suggested to be involved in the inhibition of apoptosis, organisation of the cytoskeleton and establishing the refractive
properties of the eye lens in the case of α-crystallin. How these different functions can be explained by a common mechanism
is unclear at present. However, as most of the observed phenomena involve nonnative protein, the repeatedly reported chaperone
properties of sHsps seem to be of key importance for understanding their function. In contrast to other chaperone families,
sHsps bind several nonnative proteins per oligomeric complex, thus representing the most efficient chaperone family in terms
of the quantity of substrate binding. In some cases, the release of substrate proteins from the sHsp complex is achieved in
cooperation with Hsp70 in an ATP-dependent reaction, suggesting that the role of sHsps in the network of chaperones is to
create a reservoir of nonnative refoldable protein. 相似文献
7.
Redox-regulated molecular chaperones 总被引:4,自引:0,他引:4
8.
A central dogma in biology is the conversion of genetic information into active proteins. The biosynthesis of proteins by
ribosomes and the subsequent folding of newly made proteins represent the last crucial steps in this process. To guarantee
the correct folding of newly made proteins, a complex chaperone network is required in all cells. In concert with ongoing
protein biosynthesis, ribosome-associated factors can interact directly with emerging nascent polypeptides to protect them
from degradation or aggregation, to promote folding into their native structure, or to otherwise contribute to their folding
program. Eukaryotic cells possess two major ribosome-associated systems, an Hsp70/Hsp40-based chaperone system and the functionally
enigmatic NAC complex, whereas prokaryotes employ the Trigger Factor chaperone. Recent structural insights into Trigger Factor
reveal an intricate cradle-like structure that, together with the exit site of the ribosome, forms a protected environment
for the folding of newly synthesized proteins.
Received 29 June 2005; received after revision 4 August 2005; accepted 18 August 2005 相似文献
9.
R. A. Stuart D. M. Cyr W. Neupert 《Cellular and molecular life sciences : CMLS》1994,50(11-12):1002-1011
The family of hsp70 (70 kilodalton heat shock protein) molecular chaperones plays an essential and diverse role in cellular physiology, Hsp70 proteins appear to elicit their effects by interacting with polypeptides that present domains which exhibit non-native conformations at distinct stages during their life in the cell. In this paper we review work pertaining to the functions of hsp70 proteins in chaperoning mitochondrial protein biogenesis. Hsp70 proteins function in protein synthesis, protein translocation across mitochondrial membranes, protein folding and finally the delivery of misfolded proteins to proteolytic enzymes in the mitochondrial matrix. 相似文献
10.
11.
SecB is only one of a plethora of cytosolic chaperones in E. coli whose common property is that they bind nonnative proteins. It plays a crucial role during protein export via the general
secretory pathway by modulating the partitioning of precursors between folding or aggregation and delivery to the membrane-bound
translocation apparatus. In this latter role SecB demonstrates specific binding to a unique partner, SecA. SecB has the potential
to participate in functions outside of export acting as a general nonspecific chaperone to provide buffering capacity of the
nonnative state of proteins in the cytosolic pool. We discuss the interactions of SecB with its many binding partners in light
of its recently determined structure, emphasizing both kinetic and thermodynamic parameters.
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ID="*"Corresponding author. 相似文献
12.
Mitochondria contain a specialized system of molecular chaperones that plays a critical role in the biogenesis of Fe/S centers. This Hsp70:J-protein system shows many similarities to the system found in bacteria, but the precise role of neither chaperone system has been defined. However, evidence to date suggests an interaction with the scaffold protein on which a transient Fe/S center is assembled, and thus implies a role in either assembly of the center or its transfer to recipient proteins. 相似文献
13.
Linan Xu Weibin Gong Sarah A. Cusack Huiwen Wu Harriët M. Loovers Hong Zhang Sarah Perrett Gary W. Jones 《Cellular and molecular life sciences : CMLS》2018,75(8):1445-1459
Hsp70 is a highly conserved chaperone that in addition to providing essential cellular functions and aiding in cell survival following exposure to a variety of stresses is also a key modulator of prion propagation. Hsp70 is composed of a nucleotide-binding domain (NBD) and substrate-binding domain (SBD). The key functions of Hsp70 are tightly regulated through an allosteric communication network that coordinates ATPase activity with substrate-binding activity. How Hsp70 conformational changes relate to functional change that results in heat shock and prion-related phenotypes is poorly understood. Here, we utilised the yeast [PSI +] system, coupled with SBD-targeted mutagenesis, to investigate how allosteric changes within key structural regions of the Hsp70 SBD result in functional changes in the protein that translate to phenotypic defects in prion propagation and ability to grow at elevated temperatures. We find that variants mutated within the β6 and β7 region of the SBD are defective in prion propagation and heat-shock phenotypes, due to conformational changes within the SBD. Structural analysis of the mutants identifies a potential NBD:SBD interface and key residues that may play important roles in signal transduction between domains. As a consequence of disrupting the β6/β7 region and the SBD overall, Hsp70 exhibits a variety of functional changes including dysregulation of ATPase activity, reduction in ability to refold proteins and changes to interaction affinity with specific co-chaperones and protein substrates. Our findings relate specific structural changes in Hsp70 to specific changes in functional properties that underpin important phenotypic changes in vivo. A thorough understanding of the molecular mechanisms of Hsp70 regulation and how specific modifications result in phenotypic change is essential for the development of new drugs targeting Hsp70 for therapeutic purposes. 相似文献
14.
This review describes the properties of some rare eukaryotic chaperones that each assist in the folding of only one target
protein. In particular, we describe (1) the tubulin cofactors, (2) p47, which assists in the folding of collagen, (3) α-hemoglobin
stabilizing protein (AHSP), (4) the adenovirus L4-100 K protein, which is a chaperone of the major structural viral protein,
hexon, and (5) HYPK, the huntingtin-interacting protein. These various-sized proteins (102–1,190 amino acids long) are all
involved in the folding of oligomeric polypeptides but are otherwise functionally unique, as they each assist only one particular
client. This raises a question regarding the biosynthetic cost of the high-level production of such chaperones. As the clients
of faithful chaperones are all abundant proteins that are essential cellular or viral components, it is conceivable that this
necessary metabolic expenditure withstood evolutionary pressure to minimize biosynthetic costs. Nevertheless, the complexity
of the folding pathways in which these chaperones are involved results in error-prone processes. Several human disorders associated
with these chaperones are discussed. 相似文献
15.
Various adenosine triphosphate (ATP)-dependent proteases were identified within mitochondria which mediate selective mitochondrial protein degradation and fulfill crucial functions in mitochondrial biogenesis. The matrix-localized PIM1 protease, a homologue of theEscherichia coli Lon protease, is required for respiration and maintenance of mitochondrial genome integrity. Degradation of non-native polypeptides by PIM1 protease depends on the chaperone activity of the mitochondrial Hsp70 system, posing intriguing questions about the relation between the proteolytic system and the folding machinery in mitochondria. The mitochondrial inner membrane harbors two ATP-dependent metallopeptidases, them- and thei-AAA protease, which expose their catalytic sites to opposite membrane surfaces and cooperate in the degradation of inner membrane proteins. In addition to its proteolytic activity, them-AAA protease has chaperone-like activity during the assembly of respiratory and ATP-synthase complexes. It constitutes a quality control system in the inner membrane for membrane-embedded protein complexes. 相似文献
16.
Functions and pathologies of BiP and its interaction partners 总被引:1,自引:1,他引:0
J. Dudek J. Benedix S. Cappel M. Greiner C. Jalal L. Müller R. Zimmermann 《Cellular and molecular life sciences : CMLS》2009,66(9):1556-1569
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-Sj?gren 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.
Received 20 November 2008; received after revision 09 December 2008; accepted 12 December 2008 相似文献
17.
Goh YC Yap CT Huang BH Cronshaw AD Leung BP Lai PB Hart SP Dransfield I Ross JA 《Cellular and molecular life sciences : CMLS》2011,68(9):1581-1592
Heat-shock protein 60 (Hsp60) is a highly conserved stress protein which has chaperone functions in prokaryotes and mammalian
cells. Hsp60 is associated with the mitochondria and the plasma membrane through phosphorylation by protein kinase A, and
is incorporated into lipid membranes as a protein-folding chaperone. Its diverse intracellular chaperone functions include
the secretion of proteins where it maintains the conformation of precursors and facilitates their translocation through the
plasma membrane. We report here that Hsp60 is concentrated in apoptotic membrane blebs and translocates to the surface of
cells undergoing apoptosis. Hsp60 is also enriched in platelets derived from terminally differentiated megakaryocytes and
expressed at the surface of senescent platelets. Furthermore, the exposure of monocytic U937 cells to Hsp60 enhanced their
phagocytic activity. Our results suggests that externalized Hsp60 in apoptotic cells and senescent platelets influences events
subsequent to apoptosis, such as the clearance of apoptotic cells by phagocytes. 相似文献
18.
Chun-Song Chua Huiyu Low Kian-Sim Goo T. S. Sim 《Cellular and molecular life sciences : CMLS》2010,67(10):1675-1686
It is well known that the co-chaperone p23 regulates Hsp90 chaperone activity in protein folding. In Plasmodium falciparum, a putative p23 (Pfp23) has been identified through genome analysis, but its authenticity has remained unconfirmed since
co-immunoprecipitation experiments failed to show its interaction with P. falciparum Hsp90 (PfHsp90). Thus, recombinant Pfp23 and PfHsp90 proteins purified from expressed clones were used in this study. It
was clear that Pfp23 exhibited chaperone activity by virtue of its ability to suppress citrate synthase aggregation at 45°C.
Pfp23 was also shown to interact with PfHsp90 and to suppress its ATPase activity. Analyses of modeled Pfp23-PfHsp90 protein
complex and site-directed mutagenesis further revealed strategically placed amino acid residues, K91, H93, W94 and K96, in
Pfp23 to be crucial for binding PfHsp90. Collectively, this study has provided experimental evidence for the inherent chaperone
function of Pfp23 and its interaction with PfHsp90, a sequel widely required for client protein activation. 相似文献
19.
J proteins are chief regulators of the Hsp70 family, a highly conserved family of ATPases that mediate conformational changes in a broad range of proteins. The J protein family has been the central focus of numerous prokaryote and eukaryote biologists. Common questions that arise include: How does the J protein/Hsp70 machinery support protein folding? What role do J proteins play in protein misfolding and neurodegenerative disorders? Can the J protein/ Hsp70 machinery be harnessed to provide a rational basis for recombinant protein production? The current progress that has resulted from the convergence of biochemistry with Escherichia coli and Saccharomyces cerevisiae genetics has accelerated the pace at which these questions are being elucidated. We are beginning to gain some insights into the neuronal network of J proteins. Here, we highlight recent advances in our understanding of how select J proteins harness Hsp70 s for fundamentally important conformational work in neurons. 相似文献
20.
Protein misfolding under stressful environmental conditions cause several cellular problems owing to the disturbed cellular protein homeostasis, which may further lead to neurological disorders like Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyloid lateral sclerosis and Huntington disease (HD). The presence of cellular defense mechanisms like molecular chaperones and proteasomal degradation systems prevent protein misfolding and aggregation. Molecular chaperones plays primary role in preventing protein misfolding by mediating proper native folding, unfolding and refolding of the polypeptides along with vast number of cellular functions. In past few years, the understanding of molecular chaperone mechanisms has been expanded enormously although implementation to prevent protein aggregation diseases is still deficient. We in this review evaluated major classes of molecular chaperones and their mechanisms relevant for preventing protein aggregation, specific case of α-synuclein aggregation. We also evaluate the molecular chaperone function as a novel therapeutic approach and the chaperone inhibitors or activators as small molecular drug targets. 相似文献