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1.
Hsp70 chaperones: Cellular functions and molecular mechanism 总被引:36,自引:0,他引:36
Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a large variety of protein folding processes in the cell by transient association of their substrate binding domain with short hydrophobic peptide segments within their substrate proteins. The substrate binding and release cycle is driven by the switching of Hsp70 between the low-affinity ATP bound state and the high-affinity ADP bound state. Thus, ATP binding and hydrolysis are essential in vitro and in vivo for the chaperone activity of Hsp70 proteins. This ATPase cycle is controlled by co-chaperones of the family of J-domain proteins, which target Hsp70s to their substrates, and by nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this chaperone cycle. For specific tasks the Hsp70 cycle is coupled to the action of other chaperones, such as Hsp90 and Hsp100.Received 21 October 2004; received after revision 24 November 2004; accepted 6 December 2004 相似文献
2.
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
3.
Redox-regulated molecular chaperones 总被引:4,自引:0,他引:4
4.
Chiara Giommarelli Valentina Zuco Enrica Favini Claudio Pisano Fabrizio Dal Piaz Nunziatina De Tommasi Franco Zunino 《Cellular and molecular life sciences : CMLS》2010,67(6):995-1004
Curcumin, a natural polyphenol, has been described to exhibit effects on signaling pathways, leading to induction of apoptosis.
In this study, we observed that curcumin inhibited Hsp90 activity causing depletion of client proteins implicated in survival
pathways. Based on this observation, this study was designed to investigate the cellular effects of curcumin combination with
the pan-HDAC inhibitors, vorinostat and panobinostat, which induce hyperacetylation of Hsp90, resulting in inhibition of its
chaperone function. The results showed that, at subtoxic concentrations, curcumin markedly sensitized tumor cells to vorinostat-
and panobinostat-induced growth inhibition and apoptosis. The sensitization was associated with persistent depletion of Hsp90
client proteins (EGFR, Raf-1, Akt, and survivin). In conclusion, our findings document a novel mechanism of action of curcumin
and support the therapeutic potential of curcumin/HDAC inhibitors combination, because the synergistic interaction was observed
at pharmacologically achievable concentrations, which were ineffective when each drug was used alone. 相似文献
5.
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
6.
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
7.
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
8.
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
9.
Giovanni Di Maira Francesca Brustolon Lorenzo A. Pinna Maria Ruzzene 《Cellular and molecular life sciences : CMLS》2009,66(20):3363-3373
Akt (PKB) is a critical kinase in cell-survival pathways. Its activity depends on the phosphorylation of Thr308 and Ser473,
by PDK1 and mTORC2, respectively. We found that Akt can be further stimulated through phosphorylation of Ser129 by another
kinase, CK2. Here we show that phosphorylation of Akt at Ser129 also facilitates its association with Hsp90 chaperone, thus
preventing Thr308 dephosphorylation. This is supported by the following observations: (1) phospho-Thr308 decreases when Ser129
is mutated to alanine, (2) this decrease is abolished by cell treatment with okadaic acid (to inactivate PP2A) or geldanamycin
(to inactivate Hsp90), (3) phosphorylation of Ser129 neither enhances the activity of PDK1 nor hampers the in vitro activity
of PP2A on Thr308, but increases the Hsp90 association to Akt. These data support the view that the antiapoptotic potential
of CK2 is at least in part mediated by its ability to maintain Akt in its active form. 相似文献
10.
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
11.
The mitochondrial PHB complex: roles in mitochondrial respiratory complex assembly, ageing and degenerative disease 总被引:16,自引:0,他引:16
Nijtmans LG Artal SM Grivell LA Coates PJ 《Cellular and molecular life sciences : CMLS》2002,59(1):143-155
Although originally identified as putative negative regulators of the cell cycle, recent studies have demonstrated that the
PHB proteins act as a chaperone in the assembly of subunits of mitochondrial respiratory chain complexes. The two PHB proteins,
Phb1p and Phb2p, are located in the mitochondrial inner membrane where they form a large complex that represents a novel type
of membrane-bound chaperone. On the basis of its native molecular weight, the PHB-complex should contain 12-14 copies of both
Phb1p and Phb2p. The PHB complex binds directly to newly synthesised mitochondrial translation products and stabilises them
against degradation by membrane-bound metalloproteases belonging to the family of mitochondrial triple-A proteins. Sequence
homology assigns Phb1p and Phb2p to a family of proteins which also contains stomatins, HflKC, flotillins and plant defence
proteins. However, to date only the bacterial HflKC proteins have been shown to possess a direct functional homology with
the PHB complex. Previously assigned actions of the PHB proteins, including roles in tumour suppression, cell cycle regulation,
immunoglobulin M receptor binding and apoptosis seem unlikely in view of any hard evidence in their support. Nevertheless,
because the proteins are probably indirectly involved in ageing and cancer, we assess their possible role in these processes.
Finally, we suggest that the original name for these proteins, the prohibitins, should be amended to reflect their roles as
proteins that hold badly formed subunits, thereby keeping the nomenclature already in use but altering its meaning to reflect
their true function more accurately.
Received 21 May 2001; received after revision 2 July 2001; accepted 24 July 2001 相似文献
12.
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
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.
Jadwiga Jabłońska Magda Dubińska-Magiera Teresa Jagla Krzysztof Jagla Małgorzata Daczewska 《Cellular and molecular life sciences : CMLS》2018,75(23):4341-4356
The Drosophila Hsp67Bc gene encodes a protein belonging to the small heat-shock protein (sHSP) family, identified as the nearest functional ortholog of human HSPB8. The most prominent activity of sHSPs is preventing the irreversible aggregation of various non-native polypeptides. Moreover, they are involved in processes such as development, aging, maintenance of the cytoskeletal architecture and autophagy. In larval muscles Hsp67Bc localizes to the Z- and A-bands, which suggests its role as part of the conserved chaperone complex required for Z-disk maintenance. In addition, Hsp67Bc is present at neuromuscular junctions (NMJs), which implies its involvement in the maintenance of NMJ structure. Here, we report the effects of muscle-target overexpression of Drosophila Hsp67Bc hot-spot variants Hsp67BcR126E and Hsp67BcR126N mimicking pathogenic variants of human HSPB8. Depending on the substitutions, we observed a different impact on muscle structure and performance. Expression of Hsp67BcR126E affects larval motility, which may be caused by impairment of mitochondrial respiratory function and/or by NMJ abnormalities manifested by a decrease in the number of synaptic boutons. In contrast, Hsp67BcR126N appears to be an aggregate-prone variant, as reflected in excessive accumulation of mutant proteins and the formation of large aggregates with a lesser impact on muscle structure and performance compared to the Hsp67BcR126E variant. 相似文献
15.
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
16.
Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts 总被引:21,自引:0,他引:21
Cyclosporine A therapy for prophylaxis against graft rejection revolutionized human organ transplantation. The immunosuppressant
drugs cyclosporin A (CsA), FK506 and rapamycin block T-cell activation by interfering with the signal transduction pathway.
The target proteins for CsA and FK506 were found to be cyclophilins and FK506-binding proteins, (FKBPs), respectively. They
are unrelated in primary sequence, although both are peptidyl-prolyl cis-trans isomerases catalyzing the interconversion of
peptidyl-prolyl imide bonds in peptide and protein substrates. However, the prolyl isomerase activity of these proteins is
not essential for their immunosuppressive effects. Instead, the specific surfaces of the cyclophilin-CsA and FKBP-FK506 complexes
mediate the immunosuppressive action. Moreover, the natural cellular functions of all but a few remain elusive. In some cases
it could be demonstrated that prolyl isomerization is the rate-limiting step in protein folding in vitro, but many knockout
mutants of single and multiple prolyl isomerases were viable with no detectable phenotype. Even though a direct requirement
for in vivo protein folding could not be demonstrated, some important natural substrates of the prolyl isomerases are now
known, and they demonstrate the great variety of prolyl isomerization functions in the living cell: (i) A human cyclophilin
binds to the Gag polyprotein of the human immunodeficiency virus-1 (HIV-1) virion and was found to be essential for infection
with HIV to occur, probably by removal of the virion coat. (ii) Together with heat shock protein (HSP) 90, a member of the
chaperone family, high molecular weight cyclophilins and FKBPs bind and activate steroid receptors. This example also demonstrates
that prolyl isomerases act together with other folding enzymes, for example the chaperones, and protein disulfide isomerases.
(iii) An FKBP was found to act as a modulator of an intracellular calcium release channel. (iv) Along with the cyclophilins
and FKBPs, a third class of prolyl isomerases exist, the parvulins. The human parvulin homologue Pin1 is a mitotic regulator
essential for the G2/M transition of the eukaryotic cell cycle. These findings place proline isomerases at the intersection
of protein folding, signal transduction, trafficking, assembly and cell cycle regulation.
Received 18 September 1998; received after revision 4 November 1998; accepted 23 November 1998 相似文献
17.
The small heat shock protein Hsp27 or its murine homologue Hsp25 acts as an ATP-independent chaperone in protein folding,
but is also implicated in architecture of the cytoskeleton, cell migration, metabolism, cell survival, growth/differentiation,
mRNA stabilization, and tumor progression. A variety of stimuli induce phosphorylation of serine residues 15, 78, and 82 in
Hsp27 and serines 15 and 86 in Hsp25. This post-translational modification affects some of the cellular functions of Hsp25/27.
As a consequence of the functional importance of Hsp25/27 phosphorylation, aberrant Hsp27 phosphorylation has been linked
to several clinical conditions. This review focuses on the different Hsp25/27 kinases and phosphatases that regulate the phosphorylation
pattern of Hsp25/27, and discusses the recent findings of the biological implications of these phosphorylation events in physiological
and pathological processes. Novel therapeutic strategies aimed at restoring anomalous Hsp27 phosphorylation in human diseases
will be presented. 相似文献
18.
In vitro import studies have confirmed the participation of cytosolic protein factors in the import of various precursor proteins into mitochondria. The requirement for extramitochondrial adenosine triphosphate for the import of a group of precursor proteins seems to be correlated with the chaperone activity of the cytosolic protein factors. One of the cytosolic protein factors is hsp70, which generally recognizes and binds unfolded proteins in the cytoplasm. Hsp70 keeps the newly synthesized mitochondrial precursor proteins in import-competent unfolded conformations. Another cytosolic protein factor that has been characterized is mitochondrial import stimulation factor (MSF), which seems to be specific to mitochondrial precursor proteins. MSF recognizes the mitochondrial precursor proteins, forms a complex with them and targets them to the receptors on the outer surface of mitochondria. 相似文献
19.
Marini I Moschini R Del Corso A Mura U 《Cellular and molecular life sciences : CMLS》2005,62(24):3092-3099
The chaperone behaviour of bovine serum albumin was compared with that of α-crystallin. The chaperone activity was assessed
by measuring: (i) the ability to antagonize protein aggregation induced by heat; (ii) the capability to protect the activity
of thermally stressed enzymes and (iii) the effectiveness in assisting the functional recovery of chemically denatured sorbitol
dehydrogenase. Despite the lack of structural analogies, both proteins show several functional similarities in preventing
inactivation of thermally stressed enzymes and in reactivating chemically denatured sorbitol dehydrogenase. As with α-crystallin,
the chaperone action of bovine serum albumin appears to be ATP independent. Bovine serum albumin appears significantly less
effective than α-crystallin only in preventing thermally induced protein aggregation. A possible relationship between chaperone
function and structural organization is proposed. Together, our results indicate that bovine serum albumin acts as a molecular
chaperone and that, for its particular distribution, can be included in the extracellular chaperone family.
Received 29 August 2005; received after revision 23 September 2005; accepted 12 October 2005 相似文献