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1.
The superoxide-generating NADPH oxidase: structural aspects and activation mechanism 总被引:31,自引:0,他引:31
Vignais PV 《Cellular and molecular life sciences : CMLS》2002,59(9):1428-1459
Flavocytochrome b
558
is the catalytic core of the respiratory-burst oxidase, an enzyme complex that catalyzes the NADPH-dependent reduction of
O2 into the superoxide anion O2
- in phagocytic cells. Flavocytochrome b
558
is anchored in the plasma membrane. It is a heterodimer that consists of a large glycoprotein gp91phox (phox for phagocyte oxidase) (β subunit) and a small protein p22phox (α subunit). The other components of the respiratory-burst oxidase are water-soluble
proteins of cytosolic origin, namely p67phox, p47phox, p40phox and Rac. Upon cell stimulation, they assemble with the membrane-bound
flavocytochrome b
558
which becomes activated and generates O2
-. A defect in any of the genes encoding gp91phox, p22phox, p67phox or p47phox results in chronic granulomatous disease, a
genetic disorder characterized by severe and recurrent infections, illustrating the role of O2
- and the derived metabolites H2O2 and HOCl in host defense against invading microorganisms. The electron carriers, FAD and hemes b, and the binding site for NADPH are confined to the gp91phox subunit of flavocytochrome b
558
. The p22phox subunit serves as a docking site for the cytosolic phox proteins. This review provides an overview of current
knowledge on the structural organization of the O2
--generating flavocytochrome b
558
, its kinetics, its mechanism of activation and the regulation of its biosynthesis. Homologues of gp91phox, called Nox and
Duox, are present in a large variety of non-phagocytic cells. They exhibit modest O2
--generating oxidase activity, and some act as proton channels. Their role in various aspects of signal transduction is currently
under investigation and is briefly discussed.
Received 28 May 2002; received after revision 20 June 2002; accepted 24 June 2002 相似文献
2.
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
3.
The elucidation of assembly pathways of multi-subunit membrane proteins is of growing interest in structural biology. In this
study, we provide an analysis of the assembly of the asymmetrically oriented PsaC subunit on the pseudo C2-symmetric Photosystem I core. Based on a comparison of the differences in the NMR solution structure of unbound PsaC with
that of the X-ray crystal structure of bound PsaC, and on a detailed analysis of the PsaC binding site surrounding the FX iron-sulfur cluster, two models can be envisioned for what are likely the last steps in the assembly of Photosystem I. Here,
we dissect both models and attempt to address heretofore unrecognized issues by proposing a mechanism that includes a thermodynamic
perspective. Experimental strategies to verify the models are proposed. In closing, the evolutionary aspects of the assembly
process will be considered, with special reference to the structural arrangement of the PsaC binding surface.
Received 22 October 2008; received after revision 17 November 2008; accepted 05 December 2008 相似文献
4.
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
5.
T. Jenuwein G. Laible R. Dorn G. Reuter 《Cellular and molecular life sciences : CMLS》1998,54(1):80-93
The SET domain is a 130-amino acid, evolutionarily conserved sequence motif present in chromosomal proteins that function
in modulating gene activities from yeast to mammals. Initially identified as members of the Polycomb- and trithorax-group (Pc-G and trx-G) gene families, which are required to maintain expression boundaries of homeotic selector (HOM-C) genes,
SET domain proteins are also involved in position-effect-variegation (PEV), telomeric and centromeric gene silencing, and
possibly in determining chromosome architecture. These observations implicate SET domain proteins as multifunctional chromatin
regulators with activities in both eu- and heterochromatin – a role consistent with their modular structure, which combines
the SET domain with additional sequence motifs of either a cysteine-rich region/zinc-finger type or the chromo domain. Multiple
functions for chromatin regulators are not restricted to the SET protein family, since many trx-G (but only very few Pc-G)
genes are also modifiers of PEV. Together, these data establish a model in which the modulation of chromatin domains is mechanistically
linked with the regulation of key developmental loci (e.g. HOM-C). 相似文献
6.
Pepsinogens, progastricsins, and prochymosins: structure, function, evolution, and development 总被引:12,自引:0,他引:12
Kageyama T 《Cellular and molecular life sciences : CMLS》2002,59(2):288-306
Five types of zymogens of pepsins, gastric digestive proteinases, are known: pepsinogens A, B, and F, progastricsin, and
prochymosin. The amino acid and/or nucleotide sequences of more than 50 pepsinogens other than pepsinogen B have been determined
to date. Phylogenetic analyses based on these sequences indicate that progastricsin diverged first followed by prochymosin,
and that pepsinogens A and F are most closely related. Tertiary structures, clarified by X-ray crystallography, are commonly
bilobal with a large active-site cleft between the lobes. Two aspartates in the center of the cleft, Asp32 and Asp215, function
as catalytic residues, and thus pepsinogens are classified as aspartic proteinases. Conversion of pepsinogens to pepsins proceeds
autocatalytically at acidic pH by two different pathways, a one-step pathway to release the intact activation segment directly,
and a stepwise pathway through a pseudopepsin(s). The active-site cleft is large enough to accommodate at least seven residues
of a substrate, thus forming S4 through S3′ subsites. Hydrophobic and aromatic amino acids are preferred at the P1 and P1′ positions. Interactions at additional subsites are important in some cases, for example with cleavage of κ-casein by chymosin. Two potent naturally occurring inhibitors are known: pepstatin, a pentapeptide from Streptomyces, and a unique proteinous inhibitor from Ascaris. Pepsinogen genes comprise nine exons and may be multiple, especially for pepsinogen A. The latter and progastricsin predominate
in adult animals, while pepsinogen F and prochymosin are the main forms in the fetus/infant. The switching of gene expression
from fetal/infant to adult-type pepsinogens during postnatal development is noteworthy, being regulated by several factors,
including steroid hormones.
Received 25 May 2001; received after revision 27 August 2001; accepted 30 August 2001 相似文献
7.
Adams V Lyras D Farrow KA Rood JI 《Cellular and molecular life sciences : CMLS》2002,59(12):2033-2043
Mobilisable transposons are transposable genetic elements that also encode mobilisation functions but are not in themselves
conjugative. They rely on coresident conjugative elements to facilitate their transfer to recipient cells. Clostridial mobilisable
transposons include Tn4451 and Tn4452 from Clostridium perfringens, and Tn4453a and Tn4453b from Clostridium difficile, all of which are closely related, and Tn5398 from C. difficile. The Tn4451 group of elements encodes resistance to chloramphenicol and is unusual in that transposition is dependent upon a large resolvase
protein rather than a more conventional transposase or integrase. This group of elements also encodes the mobilisation protein
TnpZ that, by acting at the RSA or oriT site located on the transposon, and in the presence of a coresident conjugative element, promotes the movement of the nonreplicating
circular intermediate and
of plasmids on which the transposon resides. The erythromycin resistance element Tn5398 is unique in that it encodes no readily identifiable transposition or mobilisation proteins. However, the element is still
capable of intraspecific transfer between C. difficile isolates, by an unknown mechanism. The detailed analysis of these mobilisable clostridial elements provides evidence that
the evolution and dissemination of antibiotic resistance genes is a complex process that may involve the interaction of genetic
elements with very different properties.
RID="*"
ID="*"Corresponding author. 相似文献
8.
The vault complex 总被引:2,自引:0,他引:2
van Zon A Mossink MH Scheper RJ Sonneveld P Wiemer EA 《Cellular and molecular life sciences : CMLS》2003,60(9):1828-1837
Vaults are large ribonucleoprotein particles found in eukaryotic cells. They are composed of multiple copies of a M
r 100,000 major vault protein and two minor vault proteins of M
r 193,000 and 240,000, as well as small untranslated RNAs of 86–141 bases. The vault components are arranged into a highly characteristic hollow barrel-like structure of 35 × 65 nm in size. Vaults are predominantly localized in the cytoplasm where they may associate with cytoskeletal elements. A small fraction of vaults are found to be associated with the nucleus. As of yet, the precise cellular function of the vault complex is unknown. However, their distinct morphology and intracellular distribution suggest a role in intracellular transport processes. Here we review the current knowledge on the vault complex, its structure, components and possible functions.Received 23 January 2003; received after revision 13 March 2003; accepted 26 March 2003 相似文献
9.
The Membrane Protein Data Bank (MPDB) is an online, searchable, relational database of structural and functional information
on integral, anchored and peripheral membrane proteins and peptides. Data originates from the Protein Data Bank and other
databases, and from the literature. Structures are based on X-ray and electron diffraction, nuclear magnetic resonance and
cryoelectron microscopy. The MPDB is searchable online by protein characteristic, structure determination method, crystallization
technique, detergent, temperature, pH, author, etc. Record entries are hyperlinked to the PDB and Pfam for viewing sequence,
three-dimensional structure and domain architecture, and for downloading coordinates. Links to PubMed are also provided. The
MPDB is updated weekly in parallel with the Protein Data Bank. Statistical analysis of MPDB records can be performed and viewed
online. A summary of the statistics as applied to entries in the MPDB is presented. The data suggest conditions appropriate
for crystallization trials with novel membrane proteins.
Received 3 August 2005; received after revision 18 September 2005; accepted 26 September 2005
This paper and the Membrane Protein Data Bank celebrate the 20th anniversary of the landmark paper in Nature (1985, 318: 618–624) describing the first ‘high-resolution’ three-dimensional structure of a membrane protein, the photosynthetic reaction
center from Rhodopseudomonas (Blastochloris) viridis. 相似文献
10.
The V(D)J recombination activating protein RAG2 consists of a six-bladed propeller and a PHD fingerlike domain, as revealed by sequence analysis 总被引:3,自引:0,他引:3
The RAG1 and RAG2 proteins play a crucial role in V(D)J recombination by cooperating to make specific double-stranded DNA
breaks at a pair of recombination signal sequences (RSSs). However, the exact function they perform has heretofore remained
elusive. Using a combination of sensitive methods of sequence analysis, we show here that the active core region of the RAG2
protein, confined to the first three quarters of its sequence, is in fact composed of a six-fold repeat of a 50-residue motif
which is related to the kelch/mipp motif. This motif, which forms a four-stranded twisted antiparallel β sheet, is arranged in a circular formation like blades of a propeller or turbine. Given the known properties of the β-propeller fold in mediating protein-protein interactions, it is proposed that this six-laded propeller structure of the RAG2
active core would play a crucial role in the tight complex formed by the RAG1 and RAG2 proteins and RSSs. Moreover, the presence
of a plant homeodomain finger-like motif in the last quarter of the RAG2 sequence suggests a potential interaction of this
domain with chromatin components.
Received 6 June 1998; accepted 9 June 1998 相似文献
11.
This review traces some of the key features of the folding of β-lactamases and their relevance to the way proteins fold in general. Studies on the enzymes have highlighted the nature and
role of equilibrium and transient condensed states. The kinetics of folding are multiphasic, and when monitored by acrylamide
quenching of the tryptophan fluorescence, an early phase provides evidence for the transient accumulation of a nonnative intermediate
involving burial of tryptophan in a nonpolar environment. Intermediate phases can be understood in terms of progressive folding
of different parts of the molecule. The later, slow phases are associated with proline isomerization in the TEM-1 enzyme and,
in its P167T mutant form, with isomerization from trans to cis of the E166 T167 peptide bond. Coupled with kinetic and X-ray crystallographic studies of the β-lactamase from Staphylococcus aureus and its D179Q mutant, it appears that the final stage of folding is that of collapse and packing of the Ω-loop on to the main body of the protein. 相似文献
12.
Integrins and cardiovascular disease 总被引:2,自引:0,他引:2
Cardiovascular diseases involve abnormal cell-cell interactions leading to the development of atherosclerotic plaque, which
when ruptured causes massive platelet activation and thrombus formation. Parts of a loose thrombus may detach to form an embolus,
blocking circulation at a more distant point. The integrins are a family of adhesive cell receptors interacting with adhesive
proteins or with counterreceptors on other cells. There is now solid evidence that the major integrin on platelets, the fibrinogen
receptor α
IIb
β
3 , has an important role in several aspects of cardiovascular diseases and that its regulated inhibition leads to a reduction
in incidence and mortality due to these disorders. The development of α
IIb
β
3 inhibitors is an important strategy of many pharmaceutical companies which foresee a large market for the treatment of acute
conditions in surgery, the symptoms of chronic conditions and, it is hoped, maybe even the successful prophylaxis of these
conditions. Although all the associated problems have not been solved, the undoubted improvements in patient care resulting
from the first of these treatments in the clinic have stimulated further research on the role of integrins on other vascular
cells in these processes and in the search for new inhibitors. Both the development of specific inhibitors and of mice with
specific integrin subunit genes ablated have contributed to a better understanding of the function of integrins in development
of the cardiovascular system. 相似文献
13.
Heat shock protein gene expression during Xenopus development 总被引:2,自引:0,他引:2
J. J. Heikkila N. Ohan Y. Tam A. Ali 《Cellular and molecular life sciences : CMLS》1997,53(1):114-121
Stress-induced heat shock protein gene expression is developmentally regulated during early embryogen esis of the frog, Xenopus laevis. For example, a number of heat shock protein genes, such as hsp70,
hsp90, and ubiquitin are not heat-inducible until after the midblastula stage of embryogenesis. Furthermore, the family of small heat shock protein
genes, hsp30, are differentially expressed after the midblastula stage as well as being regulated at the level of mRNA stability. Many
of these stress proteins are also synthesized constitutively during oogenesis and embryogenesis during which they may act
as molecular chaperones as well as being involved in sequestering proteins in an inactive state until required by the developing
embryo. Furthermore the induction of these stress protein genes has been correlated with enhanced thermoresistance. During
stressful conditions heat shock proteins probably prevent aggregation or misfolding of damaged protei
ns within the embryo. 相似文献
14.
F. E. Weber J. H. Dyer F. López García M. Werder T. Szyperski K. Wüthrich H. Hauser 《Cellular and molecular life sciences : CMLS》1998,54(7):751-759
The preform of the rabbit sterol carrier protein 2 (pre-rSCP2) was cloned, the uniformly 15N-labelled protein expressed in Escherichia coli and studied by three-dimensional 15N-resolved nuclear magnetic resonance spectroscopy. In spite of its low solubility in aqueous solution of only ∼0.3 mM, sequential
15N and 1H backbone resonance assignments were obtained for 105 out of the 143 residues. From comparison of the sequential and medium-range
nuclear Overhauser effects (NOEs) in the two proteins, all regular secondary structures previously determined in mature human
SCP2 (hSCP2) [Szyperski et al. (1993) FEBS Lett. 335: 18–26] were also identified in pre-rSCP2. Near-identity of the backbone 15N and 1H chemical shifts and 1 : 1 correspondence of 24 long-range NOEs to backbone amide groups in the two proteins show that the
residues 21 – 143 adopt the same globular fold in pre-rSCP2 and mature hSCP2. The N-terminal 20-residue leader peptide of pre-rSCP2 is flexibly disordered in solution and does not observably affect the conformation of the polypeptide segment 21 – 143.
Received 11 May 1998; accepted 15 May 1998 相似文献
15.
D. Robinette S. Wada T. Arroll M. G. Levy W. L. Miller E. J. Noga 《Cellular and molecular life sciences : CMLS》1998,54(5):467-475
Three antibacterial proteins were isolated from acid extracts of channel catfish (Ictalurus punctatus) skin by cation exchange chromatography and reverse-phase high-pressure liquid chromatography. The molecular masses of the
proteins were 15.5, 15.5 and 30 kD as determined by SDS-polyacrylamide gel electrophoresis. Mass spectrometry, amino acid
composition and amino acid sequence data suggest that the most abundant protein is closely related to histone H2B. The H2B-like
protein was inhibitory to Aeromonas hydrophila and Saprolegnia spp., which are important bacterial and fungal pathogens of fish. These findings suggest that histones may be important defensive
molecules in fish.
Received 22 December 1997; received after revision 5 March 1998; accepted 5 March 1998 相似文献
16.
Lyme disease is a multisystem illness initiated upon infection with the spirochete Borrelia burgdorferi. Whereas the majority of patients who develop Lyme arthritis may be successfully treated with antibiotic therapy, about 10%
go on to develop arthritis which persists for months to years, despite antibiotic therapy. Development of what we have termed
treatment-resistant Lyme arthritis has previously been associated with both the presence of particular major histocompatibility
complex class II alleles and immunoreactivity to the spriochetal outer surface protein A (OspA). Recently, we showed that
patients with treatment-resistant Lyme arthritis, but not patients with other forms of arthritis, generate synovial fluid
T cell responses to an immunodominant epitope of OspA and a highly homologous region of the human-lymphocyte-function-associated
antigen-1α
L chain. Identification of a bacterial antigen capable of propagating an autoimmune response against a self-antigen provides
a model of molecular mimicry in the pathogenesis of treatment-resistant Lyme arthritis.
Received 21 December 1999; received after revision 10 April 2000; accepted 11 April 2000 相似文献
17.
Protein kinase-dependent overexpression of the nuclear protein pirin in c-JUN and RAS transformed fibroblasts 总被引:1,自引:0,他引:1
Bergman AC Alaiya AA Wendler W Binetruy B Shoshan M Sakaguchi K Bergman T Kronenwett U Auer G Appella E Jörnvall H Linder S 《Cellular and molecular life sciences : CMLS》1999,55(3):467-471
Signalling via the protein kinase Raf-MEK-ERK pathway is of major importance for transformation by oncogenes. To identify
genes affected by inhibition of this pathway, c-JUN transformed rat fibroblasts were treated with a MEK1 inhibitor (PD98059) and subjected to two-dimensional gel electrophoresis
after cell lysis. Gene products with expression influenced by MEK1 inhibition were determined by mass spectrometry of fragments
from in-gel tryptic digestions. The expression of pirin, a nuclear factor I-interacting protein, was lowered after inhibition
of MEK1. Western blot analysis revealed increased expression of pirin in RAS and c-JUN transformed cells in the absence of PD98059. Inhibition of MEK1 also led to reduced expression of α-enolase, phosphoglycerate kinase, elongation factor 2 and heterogeneous nuclear ribonucleoprotein A3, the latter two being
detected as truncated proteins. In contrast, the level of ornithine aminotransferase was increased. We conclude that inhibition
of MEK1 results in major alterations of protein expression in c-JUN transformed cells, suggesting that this pathway is important for oncogene-induced phenotypic changes.
Received 30 December 1998; accepted 12 January 1999 相似文献
18.
The structure and function of heterotrimeric G protein subunits is known in considerable detail. Upon stimulation of a heptahelical
receptor by the appropriate agonists, the cognate G proteins undergo a cycle of activation and deactivation; the α-subunits and the βγ-dimers interact sequentially with several reaction partners (receptor, guanine nucleotides and effectors as well as regulatory
proteins) by exposing appropriate binding sites. For most of these domains, low molecular weight ligands have been identified
that either activate or inhibit signal transduction. These ligands include short peptides derived from receptors, G protein
subunits and effectors, mastoparan and related insect venoms, modified guanine nucleotides, suramin analogues and amphiphilic
cations. Because compounds that act on G proteins may be endowed with new forms of selectivity, we propose that G protein
subunits may therefore be considered as potential drug targets.
Received 18 September 1998; received after revision 6 November 1998; accepted 11 November 1998 相似文献
19.
Recent discoveries revealing that carbohydrate modifications play critical roles in a wide variety of biological processes
have brought wide recognition to the field of glycobiology. Growing attention has focused on the function of unusual O-linked carbohydrate modifications such as O-fucose. O-fucose modifications have been described in several different protein contexts, including epidermal growth factor-like repeats
and thrombospondin type 1 repeats. The O-fucose modifications on thrombospondin type 1 repeats have only recently been described, but the site of modification occurs
in a region proposed to play a role in cell adhesion. O-fucose modifications on epidermal growth factor-like repeats have been described as important players in several signal transduction
systems. For instance, Notch, a cell-surface signaling receptor required for many developmental events, bears multiple O-fucose saccharides on the epidermal growth factor-like repeat of its extracellular domain. The O-fucose moieties serve as a substrate for the β1,3 N-acetylglucosaminyltransferase activity of Fringe, a known modifier of Notch function. The alteration of O-fucose structures by Fringe influences the ability of Notch ligands to activate the receptor and provides a means to regulate
Notch signaling. Thus, O-fucose and Fringe provide a clear example of how carbohydrate modifications can have direct functional consequences on the
proteins they modify.
RID="*"
ID="*"Corresponding author. 相似文献