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1.
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
2.
Doerwald L van Genesen ST Onnekink C Marín-Vinader L de Lange F de Jong WW Lubsen NH 《Cellular and molecular life sciences : CMLS》2006,63(6):735-743
The mechanism of the translational thermotolerance provided by the small heat shock proteins (sHsps) αB-crystallin or Hsp27
is unknown. We show here that Hsp27, but not αB-crystallin, increased the pool of mobile stress granule-associated enhanced
green fluorescent protein (EGFP)-eukaryotic translation initiation factor (eIF)4E in heat-shocked cells, as determined by
fluorescence recovery after photobleaching. Hsp27 also partially prevented the sharp decrease in the pool of mobile cytoplasmic
EGFP-eIF4G. sHsps did not prevent the phosphorylation of eIF2α by a heat shock, but promoted dephosphorylation during recovery.
Expression of the C-terminal fragment of GADD34, which causes constitutive dephosphorylation of eIF2α, fully compensated for
the stimulatory effect of αB-crystallin on protein synthesis in heat-shocked cells, but only partially for that of Hsp27.
Our data show that sHsps do not prevent the inhibition of protein synthesis upon heat shock, but restore translation more
rapidly by promoting the dephosphorylation of eIF2α and, in the case of Hsp27, the availability of eIF4E and eIF4G.
Received 9 December 2005; received after revision 16 January 2006; accepted 23 January 2006 相似文献
3.
Parihar MS Parihar A Fujita M Hashimoto M Ghafourifar P 《Cellular and molecular life sciences : CMLS》2008,65(7-8):1272-1284
α-Synuclein is a neuron-specific protein that contributes to the pathology of Parkinson’s disease via mitochondria-related mechanisms. The present study investigated possible interaction of α-synuclein with mitochondria and
consequences of such interaction. Using SHSY cells overexpressing α-synuclein A53T mutant or wild-type, as well as isolated
rat brain mitochondria, the present study shows that α-synuclein localizes at the mitochondrial membrane. In both SHSY cells
and isolated mitochondria, interaction of α-synuclein with mitochondria causes release of cytochrome c, increase of mitochondrial calcium and nitric oxide, and oxidative modification of mitochondrial components. These findings
suggest a pivotal role for mitochondria in oxidative stress and apoptosis induced by α-synuclein.
Received 27 December 2007; received after revision 7 February 2008; accepted 8 February 2008 相似文献
4.
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
5.
Parkinson’s disease (PD) is characterized by the death of dopaminergic neurons and the presence of Lewy bodies in the substantia
nigra pars compacta. The mechanisms involved in the death of neurons as well as the role of Lewy bodies in the pathogenesis
of the disease are still unclear. Lewy bodies are made of aggregated proteins, in which α-synuclein represents their major
component. α-Synuclein interacts with synphilin-1, a protein that is also present in Lewy bodies. When expressed in cells,
synphilin-1 forms inclusions together with α-synuclein that resemble Lewy bodies. Synphilin-1 is ubiquitylated by various
E3 ubiquitin-ligases, such as SIAH, parkin and dorfin. Ubiquitylation of synphilin-1 by SIAH is essential for its aggregation
into inclusions. We recently identified a new synphilin-1 isoform, synphilin-1A, that is toxic to neurons, aggregation-prone
and accumulates in detergent-insoluble fractions of brains from α-synucleinopathy patients. Synphilin-1A inclusions recruit
both α-synuclein and synphilin-1. Aggregation of synphilin-1 and synphilin-1A seems to be protective to cells. We now discuss
several aspects of the neurobiology and pathology of synphilin-1 isoforms, focusing on possible implications for PD.
Received 26 July 2007; received after revision 19 September 2007; accepted 15 October 2007 相似文献
6.
4-Hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer's disease 总被引:3,自引:0,他引:3
Shringarpure R Grune T Sitte N Davies KJ 《Cellular and molecular life sciences : CMLS》2000,57(12):1802-1809
The amyloid β-peptide (Aβ) is a 4-kDa species derived from the amyloid precursor protein, which accumulates in the brains of patients with Alzheimer’s
disease. Although we lack full understanding of the etiology and pathogenesis of selective neuron death, considerable data
do imply roles for both the toxic Aβ and increased oxidative stress. Another significant observation is the accumulation of abnormal, ubiquitin-conjugated proteins
in affected neurons, suggesting dysfunction of the proteasome proteolytic system in these cells. Recent reports have indicated
that Aβ can bind and inhibit the proteasome, the major cytoslic protease for degrading damaged and ubiquitin-conjugated proteins.
Earlier results from our laboratory showed that moderately oxidized proteins are preferentially recognized and degraded by
the proteasome; however, severely oxidized proteins cannot be easily degraded and, instead, inhibit the proteasome. We hypothesized
that oxidatively modified Aβ might have a stronger (or weaker) inhibitory effect on the proteasome than does native Aβ. We therefore also investigated the proteasome inhibitory action of Aβ
1–40 (a peptide comprising the first 40 residues of Aβ) modified by the intracellular oxidant hydrogen peroxide, and by the lipid peroxidation product 4-hydroxynonenal (HNE). H2O2 modification of Aβ
1–40 generates a progressively poorer inhibitor of the purified human 20S proteasome. In contrast, HNE modification of Aβ
1–40 generates a progressively more selective and efficient inhibitor of the degradation of fluorogenic peptides and oxidized
protein substrates by human 20S proteasome. This interaction may contribute to certain pathological manifestations of Alzheimer’s
disease
Received 26 September 2000; accepted 26 September 2000 相似文献
7.
Molecular mechanisms of nitrosative stress-mediated protein misfolding in neurodegenerative diseases
Nitrosative and oxidative stress, associated with the generation of excessive reactive oxygen or nitrogen species, are thought
to contribute to neurodegenerative disorders. Many such diseases are characterized by conformational changes in proteins that
result in their misfolding and aggregation. Accumulating evidence implies that at least two pathways affect protein folding:
the ubiquitin-proteasome system (UPS) and molecular chaperones. Normal protein degradation by the UPS can prevent accumulation
of aberrantly folded proteins. Molecular chaperones – such as protein-disulfide isomerase, glucose-regulated protein 78, and
heat shock proteins – can provide neuroprotection from aberrant proteins by facilitating proper folding and thus preventing
their aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Here,
we present evidence for the hypothesis that nitric oxide contributes to degenerative conditions by S-nitrosylating specific chaperones or UPS proteins that would otherwise prevent accumulation of misfolded proteins.
Received 5 December 2006; received after revision 7 February 2007; accepted 15 March 2007 相似文献
8.
B. Schäfer C. Götz J. Dudek A. Hessenauer U. Matti M. Montenarh 《Cellular and molecular life sciences : CMLS》2009,66(2):339-349
Protein kinase CK2 is a highly conserved serine/threonine kinase that is ubiquitously expressed in eukaryotic cells. CK2 is
a constitutively active tetrameric enzyme composed of two catalytic α and/or α’-subunits and two regulatory β-subunits. There
is increasing evidence that the individual subunits may have independent functions and that they are asymmetrically distributed
inside the cell. To gain a better understanding of the functions of the individual subunits, we employed a yeast-two-hybrid
screen with CK2α and CK2α’. We identified the motor neuron protein KIF5C as a new binding partner for CK2. The interaction
found in the yeast-two-hybrid screen was confirmed by co-sedimentation analysis on a sucrose density gradient and by co-immunoprecipitation
analysis. Pull-down experiments and surface plasmon resonance spectrometry revealed a direct binding of KIF5C to CK2α’. Co-localization
studies with neuroblastoma cells, bone marrow and with primary neurons confirmed the biochemical analysis that KIF5C preferentially
bound to CK2α’.
Received 8 August 2008; received after revision 3 November 2008; accepted 4 November 2008 相似文献
9.
The identification of the aspartic protease BACE1 (β-secretase) was a defining event in research aimed at understanding the
molecular mechanisms that underlie Alzheimer’s disease (AD) pathogenesis. This is because BACE1 catalyses the rate limiting
step in the production of amyloid-β (Aβ) the principal component of plaque pathology in AD, the excessive production of which
is believed to be a primary cause of neurodegeneration, and cognitive dysfunction in AD. Subsequent discoveries showed that
genetic deletion of BACE1 completely abolishes Aβ production and deposition in vivo, and that BACE1 activity is significantly increased in AD brain. In this review we present current knowledge on BACE1, discussing
its structure, function and complex regulation with a view to understanding BACE1 function in the brain, and BACE1 as a target
in blocking aberrant Aβ production in AD.
Received 15 May 2008; received after revision 13 June 2008; accepted 18 June 2008 相似文献
10.
Muñoz U Bartolomé F Esteras N Bermejo-Pareja F Martín-Requero A 《Cellular and molecular life sciences : CMLS》2008,65(21):3507-3519
It has been proposed that neuroinflammation, among other factors, may trigger an aberrant neuronal cell cycle re-entry leading
to neuronal death. Cell cycle disturbances are also detectable in peripheral cells from Alzheimer’s disease (AD) patients.
We previously reported that the anti-inflammatory 15- deoxy-Δ12,14-prostaglandin J
2 (15d-PGJ
2) increased the cellular content of the cyclin-dependent kinase inhibitor p27, in lymphoblasts from AD patients. This work
aimed at elucidating the mechanisms of 15d-PGJ
2-induced p27 accumulation. Phosphorylation, half-life, and the nucleo-cytoplasmic traffic of p27 protein were altered by 15d-PGJ2
by mechanisms dependent on PI3K/Akt activity. 15d-PGJ
2 prevents the calmodulin-dependent Akt overactivation in AD lymphoblasts by blocking its binding to the 85-kDa regulatory
subunit of PI3K. These effects of 15d-PGJ
2 were not mimicked by 9,10-dihydro-15-deoxy-Δ12,14- prostaglandin J
2, suggesting that 15d-PGJ
2 acts independently of peroxisome proliferator-activated receptor γ activation and that the α,β-unsaturated carbonyl group
in the cyclopentenone ring of 15d-PGJ
2 is a requisite for the observed effects.
Received 14 July 2008; received after revision 2 September 2008; accepted 12 September 2008 相似文献
11.
Sánchez-Margalet V González-Yanes C Santos-Alvarez J Najib S 《Cellular and molecular life sciences : CMLS》1999,55(1):142-147
Insulin action is initiated by binding to its cognate receptor, which then triggers multiple cellular responses by activating
different signaling pathways. There is evidence that insulin receptor signaling may involve G protein activation in different
target cells. We have studied the activation of G proteins in rat hepatoma (HTC) cells. We found that insulin stimulated binding
of guanosine 5′-O-(3-thiotriphosphate) (GTP-γ-35S) to plasma membrane proteins of HTC cells, in a dose-dependent manner. This effect was completely blocked by pertussis toxin
treatment of the membranes, suggesting the involvement of G proteins of the Gα
i/Gα
o family. The expression of these Gα proteins was checked by Western blotting. Next, we used blocking antibodies to sort out the specific Gα protein activated by insulin stimulation. Anti-Gα
il,2 antibodies completely prevented insulin-stimulated GTP binding, whereas anti-Gα
o,i3 did not modify this effect of insulin on GTP binding. Moreover, we found physical association of the insulin receptor with
Gα
i1,2 by copurification studies. These results further support the involvement of a pertussis toxin-sensitive G protein in insulin
receptor signaling and provides some evidence of specific association and activation of Gα
i1,2 protein by insulin. These findings suggest that Gα
i1,2 proteins might be involved in insulin action.
Received 23 September 1998; received after revision 23 November 1998; accepted 25 November 1998 相似文献
12.
Glycogen synthase kinase 3β and Alzheimer’s disease: pathophysiological and therapeutic significance 总被引:3,自引:0,他引:3
Balaraman Y Limaye AR Levey AI Srinivasan S 《Cellular and molecular life sciences : CMLS》2006,63(11):1226-1235
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral dysfunction and is the leading
cause of dementia in the elderly. Several studies have implicated molecular and cellular signaling cascades involving the
serine-threonine kinase, glycogen synthase kinase β(GSK-3β) in the pathogenesis of AD. GSK-3β may play an important role in
the formation of neurofibrillary tangles and senile plaques, the two classical pathological hallmarks of AD. In this review,
we discuss the interaction between GSK-3β and several key molecules involved in AD, including the presenilins, amyloid precursor
protein, tau, and β-amyloid. We identify the signal transduction pathways involved in the pathogenesis of AD, including Wnt,
Notch, and the PI3 kinase/Akt pathway. These may be potential therapeutic targets in AD.
Received 19 December 2005; received after revision 24 January 2006; accepted 6 February 2006 相似文献
13.
Reddy SV 《Cellular and molecular life sciences : CMLS》2006,63(4):391-398
Paget’s disease of bone is a chronic focal skeletal disorder characterized by increased bone resorption by the osteoclasts.
Paramyxoviral gene products have been detected in pagetic osteoclasts. Paget’s disease is an autosomal dominant trait with
genetic heterogeneity. Several mutations in the ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1/p62) have been
identified in patients with Paget’s disease. Similarly, mutations in the valosin-containing protein (VCP) gene have been shown
to cause inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia. In addition, gene polymorphisms
and enhanced levels of cytokine/growth factors associated with Paget’s disease have been identified. However, the etiologic
factors in Paget’s disease remain elusive. A cause and effect relationship for the paramyxoviral infection and SQSTM1/ p62
gene mutations responsible for pagetic osteoclast development and disease severity are unclear. This article will highlight
the etiologic factors involved in the pathogenesis of Paget’s disease.
Received 6 October 2005; received after revision 2 November 2005; accepted 24 November 2005 相似文献
14.
Epidemiological studies establish a link between Type 2 diabetes (T2DM) and Alzheimer’s disease (AD), both leading causes
of morbidity and mortality in the elderly. These diseases also share clinical and biochemical features suggesting common pathogenic
mechanisms. Specifically, both are amyloidoses as they are characterized by fibrillar protein aggregates – amylin in T2DM
pancreatic islets, and β-amyloid (Aβ) and neurofibrillary tangles (NFTs) in AD brain. Amylin aggregation is associated with
pancreatic β-cell loss, and Aβ and NFT formation with neuronal cell loss. We discuss the possibility that amylin and Aβ exert
their toxicity by similar mechanisms, with components of the pathocascades shared, and that therapies based on amyloidogenic
properties are beneficial for both T2DM and AD.
Received 27 January 2009; received after revision 17 February 2009; accepted 23 February 2009 相似文献
15.
γ-Secretase is a promiscuous protease that cleaves bitopic membrane proteins within the lipid bilayer. Elucidating both the
mechanistic basis of γ-secretase proteolysis and the precise factors regulating substrate identification is important because
modulation of this biochemical degradative process can have important consequences in a physiological and pathophysiological
context. Here, we briefly review such information for all major classes of intramembranously cleaving proteases (I-CLiPs),
with an emphasis on γ-secretase, an I-CLiP closely linked to the etiology of Alzheimer’s disease. A large body of emerging
data allows us to survey the substrates of γ-secretase to ascertain the conformational features that predispose a peptide
to cleavage by this enigmatic protease. Because substrate specificity in vivo is closely linked to the relative subcellular compartmentalization of γ-secretase and its substrates, we also survey the
voluminous body of literature concerning the traffic of γ-secretase and its most prominent substrate, the amyloid precursor
protein.
Received 4 October 2007; received after revision 1 December 2007; accepted 7 December 2007 相似文献
16.
Inhibiting the production of amyloid-β by antagonising γ-secretase activity is currently being pursued as a therapeutic strategy
for Alzheimer’s disease (AD). However, early pre-clinical studies have demonstrated that disruption of presenilin-dependent
γ-secretase alters many presenilin-dependent processes, leading to early lethality in several AD model organisms. Subsequently,
transgenic animal studies have highlighted several gross developmental side effects arising from presenilin deficiency. Partial
knockdown or tissue-specific knockout of presenilins has identified the skin, vascular and immune systems as very sensitive
to loss of presenilin functions. A more appreciative understanding of presenilin biology is therefore demanded if γ-secretase
is to be pursued as a therapeutic target. Herein we review the current understanding of γ-secretase complexes; their regulation,
abundance of interacting partners and diversity of substrates. We also discuss regulation of the γ-secretase complexes, with
an emphasis on the functional role of presenilins in cell biology.
Received 25 July 2008; received after revision 24 November 2008; accepted 10 December 2008 相似文献
17.
Apolipoprotein E (apoE) ɛ4 allele is a genetic risk factor for late-onset familial and sporadic Alzheimer’s disease (AD).
In the central nervous system, apoE is secreted mainly by astrocytes as a constituent of high-density lipoproteins. A recent
study using apoE knockout mice provided strong evidence that apoE promotes cerebral deposition of amyloid β protein (Aβ).
However, no clear explanation of the pathogenesis of apoE-induced AD has been provided. Here we discuss two possible mechanisms
by which apoE might enhance Aβ deposition. One is the intracellular pathway in which apoE is internalized by neurons and induces
lysosomal accumulation of Aβ and amyloidogenic APP (amyloid precursor protein) fragments, leading to neuronal death. The other
is the extracellular pathway in which apoE-containing lipoproteins are trapped by Aβ1–42 deposits mobilizing soluble Aβ peptides
and consequently enlarge amyloid plaques. These two mechanisms may operate at different stages of AD pathogenesis and suggest
a chaperone-like function for the apoE molecule.
Received 4 February 1999; received after revision 9 April 1999; accepted 23 April 1999 相似文献
18.
Monocytes and their pathophysiological role in Crohn’s disease 总被引:1,自引:1,他引:0
Zhou L Braat H Faber KN Dijkstra G Peppelenbosch MP 《Cellular and molecular life sciences : CMLS》2009,66(2):192-202
Our immune system shows a stringent dichotomy, on the one hand displaying tolerance towards commensal bacteria, but on the
other hand vigorously combating pathogens. Under normal conditions the balance between flora tolerance and active immunity
is maintained via a plethora of dynamic feedback mechanisms. If, however, the balancing act goes faulty, an inappropriate
immune reaction towards an otherwise harmless intestinal flora causes disease, Crohn’s disease for example. Recent developments
in the immunology and genetics of mucosal diseases suggest that monocytes and their derivative cells play an important role
in the pathophysiology of Crohn’s disease. In our review, we summarize the recent studies to discuss the dual function of
monocytes - on the one hand the impaired monocyte function initiating Crohn’s disease, and on the other hand the overactivation
of monocytes and adaptive immunity maintaining the disease. With a view to developing new therapies, both aspects of monocyte
functions need to be taken into account.
Received 1 June 2008; received after revision 24 July 2008; accepted 13 August 2008 相似文献
19.
V. Bellotti P. Mangione M. Stoppini 《Cellular and molecular life sciences : CMLS》1999,55(6-7):977-991
The physiological metabolism of proteins guarantees that different cellular compartments contain the appropriate concentration
of proteins to perform their biological functions and, after a variable period of wear and tear, mediates their natural catabolism.
The equilibrium between protein synthesis and catabolism ensures an effective turnover, but hereditary or acquired abnormalities
of protein structure can provoke a premature loss of biological function, an accelerated catabolism and diseases caused by
the loss of an irreplaceable function. In certain proteins, abnormal structure and metabolism are associated with a strong
tendency to self-aggregation into a polymeric fibrillar structure, and in these cases the disease is not principally caused
by the loss of an irreplaceable function but by the action of this new biological entity. Amyloid fibrils are an apparently
inert, insoluble, mainly extracellular protein polymer that kills the cell without tissue necrosis but by activation of the
apoptotic mechanism. We analyzed the data reported so far on the structural and functional properties of four prototypic proteins
with well-known biological functions (lysozyme, transthyretin, β2-microglobulin and apolipoprotein AI) that are able to create
amyloid fibrils under certain conditions, with the perspective of evaluating whether the achievement of biological function
favors or inhibits the process of fibril formation. Furthermore, studying the biological functions carried out by amyloid
fibrils reveals new types of protein-protein interactions in the transmission of messages to cells and may provide new ideas
for effective therapeutic strategies.
Received 9 November 1998; received after revision 15 January 1999; accepted 15 January 1999 相似文献
20.
Nabeshima Y 《Cellular and molecular life sciences : CMLS》2008,65(20):3218-3230
The traditional view of calcium homeostasis is that it is maintained by two essential reactions. First, changes in extracellular
Ca2+ are sensed in several distinct cell types, stimulating the secretion of parathyroid hormone (PTH), 1,25(OH)2 D and calcitonin in response to the body’s requirement. Second, these calcitropic hormones then act on the calcium-translocating
cells of the kidney, bone, and intestine to restore calcium balance. Recent progress indicates that α-Klotho and fibroblast
growth factor (FGF) 23 are key players that integrate the multi-step regulatory system of calcium homeostasis that rapidly
adjusts the extracellular calcium concentration and continuously maintains its concentration within a narrow physiological
range. α-Klotho and FGF23 are also found to be major players in the regulatory system of phosphate homeostasis. Here, the
demonstration of the molecular functions of α-Klotho and FGF23 has recently given new insight into the field of calcium and
phosphate homeostasis.
Received 3 April 2008; received after revision 23 May 2008; accepted 5 June 2008 相似文献