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1.
Activation of innate immunity by lysozyme fibrils is critically dependent on cross-β sheet structure
Adelin Gustot Vincent Raussens Morgane Dehousse Mireille Dumoulin Clare E. Bryant Jean-Marie Ruysschaert Caroline Lonez 《Cellular and molecular life sciences : CMLS》2013,70(16):2999-3012
Inflammation occurs in many amyloidoses, but its underlying mechanisms remain enigmatic. Here we show that amyloid fibrils of human lysozyme, which are associated with severe systemic amyloidoses, induce the secretion of pro-inflammatory cytokines through activation of the NLRP3 (NLR, pyrin domain containing 3) inflammasome and the Toll-like receptor 2, two innate immune receptors that may be involved in immune responses associated to amyloidoses. More importantly, our data clearly suggest that the induction of inflammatory responses by amyloid fibrils is linked to their intrinsic structure, because the monomeric form and a non-fibrillar type of lysozyme aggregates are both unable to trigger cytokine secretion. These lysozyme species lack the so-called cross-β structure, a characteristic structural motif common to all amyloid fibrils irrespective of their origin. Since fibrils of other bacterial and endogenous proteins have been shown to trigger immunological responses, our observations suggest that the cross-β structural signature might be recognized as a generic danger signal by the immune system. 相似文献
2.
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
3.
Alzheimer’s disease (AD) is a neurodegenerative disorder occurring in the elderly. It is widely accepted that the amyloid
beta peptide (Aβ) aggregation and especially the oligomeric states rather than fibrils are involved in AD onset. We used infrared
spectroscopy to provide structural information on the entire aggregation pathway of Aβ(1–40), starting from monomeric Aβ to
the end of the process, fibrils. Our structural study suggests that conversion of oligomers into fibrils results from a transition
from antiparallel to parallel β-sheet. These structural changes are described in terms of H-bonding rupture/formation, β-strands
reorientation and β-sheet elongation. As antiparallel β-sheet structure is also observed for other amyloidogenic proteins
forming oligomers, reorganization of the β-sheet implicating a reorientation of β-strands could be a generic mechanism determining
the kinetics of protein misfolding. Elucidation of the process driving aggregation, including structural transitions, could
be essential in a search for therapies inhibiting aggregation or disrupting aggregates. 相似文献
4.
In amyloid related diseases, proteins form fibrillar aggregates with highly ordered -sheet structure regardless of their native conformations. Formation of such amyloid fibrils can be reproducible in vitro using isolated proteins/peptides, suggesting that amyloid fibril formation takes place as a result of protein conformational change. In vitro studies revealed that perturbation of the native structure is important for the fibril formation, and it is suggested that the mechanisms of amyloid fibril formation share the mechanisms of protein folding. In particular, amyloid fibril formation is similar to one of the common features of proteins, i.e. amorphous aggregation upon partial unfolding, which is likely driven by hydrophobic interactions through exposed protein interior. However, these molecular associations are distinct phenomena, and identifying factors that lead to amyloid fibril formation would precede our understanding of the mechanisms of amyloid fibrillization. The necessity of understanding the nature of protein denatured states is also suggested.Received 6 July 2003; accepted 19 August 2003 相似文献
5.
Bjarnadóttir TK Fredriksson R Schiöth HB 《Cellular and molecular life sciences : CMLS》2007,64(16):2104-2119
G protein-coupled receptors (GPCRs) are a diverse superfamily of membrane-bound receptors. The second largest subgroup of
GPCRs, the Adhesion GPCRs, has 33 members in humans. Phylogenetic analysis of the entire repertoire of the seven transmembrane- domain (7TM)
regions of GPCRs shows that the Adhesion GPCRs form a distinct family. Adhesion GPCRs are characterised by (1) long N termini with multiple functional domains often found in other proteins such as tyrosine
kinases, integrins and cadherins, (2) highly complex genomic structure with multiple introns and splice variants and (3) a
7TM region that has no clear similarities with 7TM from other GPCRs. Several Adhesion GPCRs are known to have a role in the immune system but it is becoming more evident that many have important roles in the
CNS. We speculate that the overall structural construction of the Adhesion GPCRs allows them to participate in different types of cell guidance.
Received 8 February 2007; received after revision 21 March 2007; accepted 25 April 2007 相似文献
6.
Improper protein folding (misfolding) can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates.
The major lens protein, α-crystallin, is a member of the small heat-shock protein (sHsp) family of intracellular molecular
chaperone proteins that prevent protein aggregation. Whilst the chaperone activity of sHsps against amorphously aggregating
proteins has been well studied, its action against fibril-forming proteins has received less attention despite the presence
of sHsps in deposits found in fibril-associated diseases (e.g. Alzheimer’s and Parkinson’s). In this review, the literature
on the interaction of αB-crystallin and other sHsps with fibril-forming proteins is summarized. In particular, the ability
of sHsps to prevent fibril formation, their mechanisms of action and the possible in vivo consequences of such associations are discussed. Finally, the fibril-forming propensity of the crystallin proteins and its
implications for cataract formation are described along with the potential use of fibrillar crystallin proteins as bionanomaterials.
Received 13 June 2008; received after revision 29 July 2008; accepted 05 August 2008 相似文献
7.
R. J. S. Viana A. F. Nunes R. E. Castro R. M. Ramalho J. Meyerson S. Fossati J. Ghiso A. Rostagno C. M. P. Rodrigues 《Cellular and molecular life sciences : CMLS》2009,66(6):1094-1104
The vasculotropic E22Q mutant of the amyloid-β (Aβ) peptide is associated with hereditary cerebral hemorrhage with amyloidosis
Dutch type. The cellular mechanism(s) of toxicity and nature of the AβE22Q toxic assemblies are not completely understood.
Comparative assessment of structural parameters and cell death mechanisms elicited in primary human cerebral endothelial cells
by AβE22Q and wild-type Aβ revealed that only AβE22Q triggered the Bax mitochondrial pathway of apoptosis. AβE22Q neither
matched the fast oligomerization kinetics of Aβ42 nor reached its predominant β-sheet structure, achieving a modest degree
of oligomerization with a secondary structure that remained a mixture of β and random conformations. The endogenous molecule
tauroursodeoxycholic acid (TUDCA) was a strong modulator of AβE22Q-triggered apoptosis but did not significantly change the
secondary structures and fibrillogenic propensities of Aβ peptides. These data dissociate the pro-apoptotic properties of
Aβ peptides from their distinct mechanisms of aggregation/fibrillization in vitro, providing new perspectives for modulation of amyloid toxicity.
Received 20 November 2008; received after revision 12 December 2008; accepted 12 January 2009 相似文献
8.
Monogenetic determinants of Alzheimer's disease: APP mutations 总被引:2,自引:0,他引:2
A. M. Goate 《Cellular and molecular life sciences : CMLS》1998,54(9):897-901
Mutations within exons 16 and 17 of the β-amyloid precursor protein (APP) gene were the first known cause of familial Alzheimer's disease. These mutations are rare
and have been reported in a handful of families exhibiting autosomal dominant inheritance of Alzheimer's disease with age
of onset around 50 years. In vitro and in vivo studies have demonstrated that each of these mutations alters proteolytic processing
of APP, resulting in an increase in the production of Aβ42, a highly fibrillogenic peptide, that spontaneously aggregates and deposits in the brain. Transgenic mice carrying a mutant
human APP gene also show age-dependent β-amyloid (Aβ) deposition in the brain. The rate of deposition in these mice can be modified by apolipoprotein E expression. 相似文献
9.
A. Rostagno J. L. Holton T. Lashley T. Revesz Jorge Ghiso 《Cellular and molecular life sciences : CMLS》2010,67(4):581-600
Cerebral amyloid diseases are part of a complex group of chronic and progressive entities bracketed together under the common
denomination of protein folding disorders and characterized by the intra- and extracellular accumulation of fibrillar aggregates.
Of the more than 25 unrelated proteins known to produce amyloidosis in humans only about a third of them are associated with
cerebral deposits translating in cognitive deficits, dementia, stroke, cerebellar and extrapyramidal signs, or a combination
thereof. The familial forms reviewed herein, although infrequent, provide unique paradigms to examine the role of amyloid
in the mechanism of disease pathogenesis and to dissect the link between vascular and parenchymal amyloid deposition and their
differential contribution to neurodegeneration. 相似文献
10.
Immunoglobulin light chains are the precursor proteins for fibrils that are formed during primary amyloidosis and in amyloidosis associated with multiple myeloma. As found for the approximately 20 currently described forms of focal, localized, or systemic amyloidoses, light chain-related fibrils extracted from physiological deposits are invariably associated with glycosaminoglycans, predominantly heparan sulfate. Other amyloid-related proteins are either structurally normal, such as beta2-microglobulin and islet amyloid polypeptide, fragments of normal proteins such as serum amyloid A protein or the precursor protein of the beta peptide involved in Alzheimer's disease, or are inherited forms of single amino acid variants of a normal protein such as found in the familial forms of amyloid associated with transthyretin. In contrast, the primary structures of light chains involved in fibril formation exhibit extensive mutational diversity rendering some proteins highly amyloidogenic and others non-pathological. The interactions between light chains and glycosaminoglycans are also affected by amino acid variation and may influence the clinical course of disease by enhancing fibril stability and contributing to resistance to protease degradation. Relatively little is currently known about the mechanisms by which glycosaminoglycans interact with light chains and light-chain fibrils. It is probable that future studies of this uniquely diverse family of proteins will continue to shed light on the processes of amyloidosis, and contribute as well to a greater understanding of the normal physiological roles of glycosaminoglycans. 相似文献
11.
12.
Jedrzejas MJ 《Cellular and molecular life sciences : CMLS》2007,64(21):2799-2822
Bacteria present a variety of molecules either on their surface or in a cell-free form. These molecules take part in numerous
processes in the interactions with their host, with its tissues and other molecules. These molecules are essential to bacterial
pathogenesis either during colonization or the spread/invasion stages, and most are virulence factors. This review is focused
on such molecules using Streptococcus pneumoniae, a Gram-positive bacterium, as an example. Selected surface proteins are introduced, their structure described, and, whenever
available, their mechanisms of function on an atomic level are explained. Such mechanisms for hyaluronate lyase, pneumococcal
surface protein A, pneumolysin, histidine-triad and fibronectin-binding proteins are discussed. Elucidation of molecular mechanisms
of virulence factors is essential for the understanding of bacteria and their functional properties. Structural biology appears
pivotal for these studies, as structural and mechanistic insights facilitate rational approach to the development of new treatments.
Received 12 March 2007; received after revision 28 June 2007; accepted 18 July 2007 相似文献
13.
Three-dimensional structure of annexins 总被引:4,自引:0,他引:4
Annexins constitute a family of structurally related calcium- and phospholipid-binding proteins whose molecular structure
has been investigated in detail in the crystalline and membrane-bound form. Their polypeptide chain is folded into four or
eight α-helical domains of similar structure with a central hydrophilic pore. Bound to phospholipid membranes, the four-domain arrangement
of the annexin molecule is conserved. A peripheral binding mode has been well documented by electron microscopy and a variety
of other techniques. 相似文献
14.
Rostagno A Tomidokoro Y Lashley T Ng D Plant G Holton J Frangione B Revesz T Ghiso J 《Cellular and molecular life sciences : CMLS》2005,62(16):1814-1825
The importance of cerebral amyloid deposition in the mechanism of neurodegeneration is still debatable. Classic arguments are usually centered on amyloid β(Aβ) and its role in the neuronal loss characteristic of Alzheimer’s disease, the most common form of human cerebral amyloidosis. Two non-Aβ cerebral amyloidoses, familial British and Danish dementias (FBD and FDD), share many aspects of Alzheimer’s disease, including the presence of neurofibrillary tangles, parenchymal preamyloid and amyloid deposits, cerebral amyloid angiopathy and a variety of amyloid-associated proteins and inflammatory components. Both early-onset conditions are linked to specific mutations at or near the stop codon of the chromosome 13 gene BRI2 that cause generation of longer-than-normal protein products. Furin-like processing of these longer precursors releases two de novo-created peptides, ABri and ADan, which deposit as amyloid fibrils in FBD and FDD, respectively. Due to the similar pathology generated by completely unrelated amyloid subunits, FBD and FDD, collectively referred to as chromosome 13 dementias, constitute alternative models for studying the role of amyloid deposition in the mechanism of neuronal cell death.Received 4 March 2005; received after revision 24 April 2005; accepted 26 April 2005 相似文献
15.
Carl Peter J. Maury 《Cellular and molecular life sciences : CMLS》2018,75(9):1499-1507
A crucial stage in the origin of life was the emergence of the first molecular entity that was able to replicate, transmit information, and evolve on the early Earth. The amyloid world hypothesis posits that in the pre-RNA era, information processing was based on catalytic amyloids. The self-assembly of short peptides into β-sheet amyloid conformers leads to extraordinary structural stability and novel multifunctionality that cannot be achieved by the corresponding nonaggregated peptides. The new functions include self-replication, catalytic activities, and information transfer. The environmentally sensitive template-assisted replication cycles generate a variety of amyloid polymorphs on which evolutive forces can act, and the fibrillar assemblies can serve as scaffolds for the amyloids themselves and for ribonucleotides proteins and lipids. The role of amyloid in the putative transition process from an amyloid world to an amyloid–RNA–protein world is not limited to scaffolding and protection: the interactions between amyloid, RNA, and protein are both complex and cooperative, and the amyloid assemblages can function as protometabolic entities catalyzing the formation of simple metabolite precursors. The emergence of a pristine amyloid-based in-put sensitive, chiroselective, and error correcting information-processing system, and the evolvement of mutualistic networks were, arguably, of essential importance in the dynamic processes that led to increased complexity, organization, compartmentalization, and, eventually, the origin of life. 相似文献
16.
Sumoylation regulates diverse biological processes 总被引:8,自引:0,他引:8
Zhao J 《Cellular and molecular life sciences : CMLS》2007,64(23):3017-3033
Ten years after its discovery, the small ubiquitin-like protein modifier (SUMO) has emerged as a key regulator of proteins.
While early studies indicated that sumoylation takes place mainly in the nucleus, an increasing number of non-nuclear substrates
have recently been identified, suggesting a wider stage for sumoylation in the cell. Unlike ubiquitylation, which primarily
targets a substrate for degradation, sumoylation regulates a substrate’s functions mainly by altering the intracellular localization,
protein-protein interactions or other types of post-translational modifications. These changes in turn affect gene expression,
genomic and chromosomal stability and integrity, and signal transduction. Sumoylation is counter-balanced by desumoylation,
and well-balanced sumoylation is essential for normal cellular behaviors. Loss of the balance has been associated with a number
of diseases. This paper reviews recent progress in the study of SUMO pathways, substrates, and cellular functions and highlights
important findings that have accelerated advances in this study field and link sumoylation to human diseases.
Received 19 March 2007; received after version 16 July 2007; accepted 1 August 2007 相似文献
17.
Hippocrates’ assertion that ‘what the lance does not heal, fire will’ underscores the fact that for thousands of years heat
has been used to treat a variety of diseases, including cancer. Indeed, spontaneous tumor remission has been observed in patients
following feverish infection [1], and expression of activated oncogenes, such as Ras, can render tumor cells sensitive to
heat compared with normal cells [2, 3]. In the past, a primary drawback to the use of heat as a clinical therapy was the inability
to selectively focus heat to tumors in situ. Of late, however, several approaches have been devised to deliver heat more precisely, including the use of heated nanoparticles,
making hyperthermia a more clinically tractable treatment option [4, 5]. Despite these practical advances, the mechanisms
responsible for heat shock-induced cell death remain controversial and ill-defined. In this Visions and Reflections we discuss recent findings surrounding the initiation of heat shock-induced apoptosis, and propose future areas of research.
Received 17 March 2007; received after revision 25 April 2007; accepted 22 May 2007 相似文献
18.
Anti-amyloidogenic therapies: strategies for prevention and treatment of Alzheimer’s disease 总被引:1,自引:1,他引:0
Deposition of amyloid β-protein (Aβ) in the brain is an early and invariant neuropathological feature of Alzheimer’s disease
(AD). The current search for anti-AD drugs is mainly focused on modification of the process of accumulation of Aβ in the brain.
Here, we review four anti-amyloidogenic strategies: (i) reduction of Aβ production, which has mainly been approached with
secretase inhibition, (ii) promotion of the Aβ degrading catabolic pathway, including an Aβ degrading enzyme, neprilysin,
(iii) immunotherapy for Aβ and (iv) inhibition of Aβ aggregation. We have reported that AD patients have a favorable molecular
environment for Aβ aggregation and that various compounds, such as polyphenols, interfere with Aβ aggregation and destabilize
preformed Aβ fibrils.
Received 21 December 2005; received after revision 14 February 2006; accepted 29 March 2006 相似文献
19.
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
20.
Nakashima K Nishino A Horikawa Y Hirose E Sugiyama J Satoh N 《Cellular and molecular life sciences : CMLS》2011,68(9):1623-1631
The native form of cellulose is a fibrillar composite of two crystalline phases, the triclinic Iα and monoclinic Iβ allomorphs. Allomorph ratios are species-specific, and this gives rise to natural structural variations in cellulose crystals.
However, the mechanisms contributing to crystal formation remain unknown. We show that the two crystalline phases of cellulose
are tailored to distinct structures during different developmental stages of the tunicate chordate Oikopleura dioica. Larval cellulose consisting of Iα allomorph constitutes the body cuticle fin, whereas adult cellulose consisting of Iβ allomorph frames a mucous filter-feeding device, the “house.” Both structures are secreted from the epidermis in accordance
with the mutually exclusive expression patterns of two distinct putative cellulose synthase genes. We discuss a possible linkage
between structural variations of the crystalline phases of cellulose and the underlying evolutionary genetics of cellulose
biosynthesis. 相似文献