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1.
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
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Sanchez-Perez I Rodriguez-Hernandez CJ Manguan-García C Torres A Perona R Murguía JR 《Cellular and molecular life sciences : CMLS》2004,61(6):700-708
The immunosuppressants tacrolimus (FK506) and cyclosporin A (CsA) have increased the survival rates in organ transplantation. Both drugs inhibit the protein phosphatase calcineurin (CaN) in activated T cells, exhibiting similar side-effects. Diabetes is observed more often in FK506 than CsA therapy, probably due to inhibition of new molecular targets other than CaN. We studied FK506 toxicity in mammalian cells. FK506, but not CsA, regulated p38 activation by osmotic stress, and decreased viability in osmostressed cells. In addition, FK506 treatment strongly increased the phosphorylation of the eukaryotic initiation factor-2a (eIF-2a) subunit. eIF-2a phosphorylation, p38 inhibition and cell lethality were relieved by addition of excess amino acids to the medium, suggesting that amino acid availability mediated FK506 toxicity. Therefore, these FK506-dependent responses could be relevant to the non-therapeutic effects of FK506 therapy.Received 16 October 2003; received after revision 8 January 2004; accepted 14 January 2004 相似文献
4.
Composition and conservation of the telomeric complex 总被引:6,自引:0,他引:6
The telomere is composed of telomeric DNA and telomere-associated proteins. Recently, many telomere-associated proteins have been identified, and various telomere functions have been uncovered. In budding yeast, scRap1 binds directly to telomeric DNA, and other telomere regulators (Sir proteins and Rif proteins) are recruited to the telomeres by interacting with scRap1. Cdc13 binds to the most distal end of the chromosome and recruits telomerase to the telomeres. In fission yeast and humans, TTAGGG repeat binding factor (TRF) family proteins bind directly to telomeric DNA, and Rap1 proteins and other telomere regulators are recruited to the telomeres by interacting with the TRF family proteins. Both organisms have Pot1 proteins at the most distal end of the telomere instead of a budding-yeast Cdc13-like protein. Therefore, fission yeast and humans have in part common telomeric compositions that differ from that of budding yeast, a result that suggests budding yeast has lost some telomere components during the course of evolution. 相似文献
5.
Immunophilins: for the love of proteins 总被引:1,自引:0,他引:1
Barik S 《Cellular and molecular life sciences : CMLS》2006,63(24):2889-2900
Immunophilins are chaperones that may also exhibit peptidylprolyl isomerase (PPIase) activity. This review summarizes our
knowledge of the two largest families of immunophilins, namely cyclophilin and FK506-binding protein, and a novel chimeric
dual-family immunophilin, named FK506- and cyclosporin-binding protein (FCBP). The larger members of each family are modular
in nature, consisting of multiple PPIase and/or protein-protein interaction domains. Despite the apparent difference in their
sequence and three-dimensional structure, the three families encode similar enzymatic and biological functions. Recent studies
have revealed that many immunophilins possess a chaperone function independent of PPIase activity. Knockout animal studies
have confirmed multiple essential roles of immunophilins in physiology and development. An immunophilin is indeed a natural
‘protein-philin’ (Greek ‘philin’ = friend) that interacts with proteins to guide their proper folding and assembly.
Received: 7 May 2006; received after revision 3 July 2006; accepted 24 August 2006 相似文献
6.
McTaggart SJ 《Cellular and molecular life sciences : CMLS》2006,63(3):255-267
Isoprenoids are synthesized in all living organisms and are incorporated into diverse classes of end-products that participate
in a multitude of cellular processes relating to cell growth, differentiation, cytoskeletal function and vesicle trafficking.
In humans, the non-sterol isoprenoids, farnesyl pyrophosphate and geranylgeranyl-pyrophosphate, are synthesized via the mevalonate
pathway and are covalently added to members of the small G protein superfamily. Isoprenylated proteins have key roles in membrane
attachment and protein functionality, have been shown to have a central role in some cancers and are likely also to be involved
in the pathogenesis and progression of atherosclerosis and Alzheimer disease. This review details current knowledge on the
biosynthesis of isoprenoids, their incorporation into proteins by the process known as prenylation and the complex regulatory
network that controls these proteins. An improved understanding of these processe is likely to lead to the development of
novel therapies that will have important implications for human health and disease.
Received 5 July 2005; received after revision 17 October 2005; accepted 22 October 2005 相似文献
7.
Cristina Lanni Stefano Govoni Adele Lucchelli Cinzia Boselli 《Cellular and molecular life sciences : CMLS》2009,66(18):2985-3008
Clinical depression is viewed as a physical and psychic disease process having a neuropathological basis, although a clear
understanding of its ethiopathology is still missing. The observation that depressive symptoms are influenced by pharmacological
manipulation of monoamines led to the hypothesis that depression results from reduced availability or functional deficiency
of monoaminergic transmitters in some cerebral regions. However, there are limitations to current monoamine theories related
to mood disorders. Recently, a growing body of experimental data has showed that other classes of endogenous compounds, such
as neuropeptides and amino acids, may play a significant role in the pathophysiology of affective disorders. With the development
of neuroscience, neuronal networks and intracellular pathways have been identified and characterized, describing the existence
of the interaction between monoamines and receptors in turn able to modulate the expression of intracellular proteins and
neurotrophic factors, suggesting that depression/antidepressants may be intermingled with neurogenesis/neurodegenerative processes. 相似文献
8.
Chemokines are a vertebrate-specific group of small molecules that regulate cell migration and behaviour in diverse contexts.
So far, around 50 chemokines have been identified in humans, which bind to 18 different chemokine receptors. These are members
of the seven-transmembrane receptor family. Initially, chemokines were identified as modulators of the immune response. Subsequently,
they were also shown to regulate cell migration during embryonic development. Here, we discuss the influence of chemokines
and their receptors on angiogenesis, or the formation of new blood vessels. We highlight recent advances in our understanding
of how chemokine signalling might directly influence endothelial cell migration. We furthermore examine the contributions
of chemokine signalling in immune cells during this process. Finally, we explore possible implications for disease settings,
such as chronic inflammation and tumour progression. 相似文献
9.
Anne Berna François Bernier Eric Chabrière Mikael Elias Ken Scott Andrew Suh 《Cellular and molecular life sciences : CMLS》2009,66(14):2205-2218
DING proteins, identified mainly by their eponymous N-terminal sequences, are ubiquitous in living organisms. Amongst bacteria,
they are common in pseudomonads, and have been characterised with respect to genetics and structure. They form part of a wider
family of phosphate-binding proteins, with emerging roles in phosphate acquisition and pathogenicity. Many DING proteins have
been isolated in eukaryotes, in which they have been associated with very diverse biological activities, often in the context
of possible signalling roles. Disease states in which DING proteins have been implicated include rheumatoid arthritis, lithiasis,
atherosclerosis, some tumours and tumour-associated cachexia, and bacterial and viral adherence. Complete genetic and structural
characterisation of eukaryotic DING genes and proteins is still lacking, though the phosphate-binding site seems to be conserved.
Whether as bacterial proteins related to bacterial pathogenicity, or as eukaryotic components of biochemical signalling systems,
DING proteins require further study.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
10.
A vast number of structurally diverse bitter compounds need to be detected by a subfamily of only approximately 25 human bitter receptors. Failure in detecting them might be lethal, since some naturally occurring bitter compounds, such as strychnine, are very toxic. This review presents an overview about the enormous progress in the field of mammalian bitter taste research with special emphasis on humans, if data were available. It summarizes the current knowledge about the anatomical basis for bitter taste perception, intracellular signal transduction, evolution, expression and polymorphisms of hTAS2R genes, and the molecular basis for the recognition of bitter compounds. 相似文献
11.
Structure, function and evolution of antifreeze proteins 总被引:16,自引:0,他引:16
Antifreeze proteins bind to ice crystals and modify their growth. These proteins show great diversity in structure, and they
have been found in a variety of organisms. The ice-binding mechanisms of antifreeze proteins are not completely understood.
Recent findings on the evolution of antifreeze proteins and on their structures and mechanisms of action have provided new
understanding of these proteins in different contexts. The purpose of this review is to present the developments in contrasting
research areas and unite them in order to gain further insight into the structure and function of the antifreeze proteins.
Received 2 September 1998; received after revision 21 October 1998; accepted 2 November 1998 相似文献
12.
Reticulons (RTNs) are membrane-spanning proteins sharing a typical domain named reticulon homology domain (RHD). RTN genes
have been identified in all eukaryotic organisms examined so far, and the corresponding proteins have been found predominantly
associated to the endoplasmic reticulum membranes. In animal and yeast, in which knowledge of the protein family is more advanced,
RTNs are involved in numerous cellular processes such as apoptosis, cell division and intracellular trafficking. Up to now,
a little attention has been paid to their plant counterparts, i.e., RTNLBs. In this review, we summarize the data available for RTNLB proteins and, using the data obtained with animal and
yeast models, several functions for RTNLBs in plant cells are proposed and discussed.
Received 01 July 2008; received after revision 08 September 2008; accepted 30 September 2008 相似文献
13.
Cyclosporine A (CsA) is an immunosuppressive cyclic peptide that binds with a high affinity to 18 kDa human cyclophilin-A
(hCyPA). CsA and its several natural derivatives have some pharmacological potential in treatment of diverse immune disorders.
More than 20 paralogues of CyPA are expressed in the human body while expression levels and functions of numerous ORFs encoding
cyclophilin-like sequences remain unknown. Certain derivatives of CsA devoid of immunosuppressive activity may have some potential
in treatments of Alzheimer diseases, Hepatitis C and HIV infections, amyotrophic lateral sclerosis, congenital muscular dystrophy,
asthma and various parasitic infections. Here, we discuss structural and functional aspects of the human cyclophilins and
their interaction with various intra-cellular targets that can be under the control of CsA or its complexes with diverse cyclophilins
that are selectively expressed in different cellular compartments. Some molecular aspects of the cyclophilins expressed in
parasites invading humans and causing diseases were also analyzed. 相似文献
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Vedrana Filić Maja Marinović Jan Faix Igor Weber 《Cellular and molecular life sciences : CMLS》2014,71(15):2775-2785
Proteins are typically categorized into protein families based on their domain organization. Yet, evolutionarily unrelated proteins can also be grouped together according to their common functional roles. Sequestering proteins constitute one such functional class, acting as macromolecular buffers and serving as an intracellular reservoir ready to release large quantities of bound proteins or other molecules upon appropriate stimulation. Another functional protein class comprises effector proteins, which constitute essential components of many intracellular signal transduction pathways. For instance, effectors of small GTP-hydrolases are activated upon binding a GTP-bound GTPase and thereupon participate in downstream interactions. Here we describe a member of the IQGAP family of scaffolding proteins, DGAP1 from Dictyostelium, which unifies the roles of an effector and a sequestrator in regard to the small GTPase Rac1. Unlike classical effectors, which bind their activators transiently leading to short-lived signaling complexes, interaction between DGAP1 and Rac1-GTP is stable and induces formation of a complex with actin-bundling proteins cortexillins at the back end of the cell. An oppositely localized Rac1 effector, the Scar/WAVE complex, promotes actin polymerization at the cell front. Competition between DGAP1 and Scar/WAVE for the common activator Rac1-GTP might provide the basis for the oscillatory re-polarization typically seen in randomly migrating Dictyostelium cells. We discuss the consequences of the dual roles exerted by DGAP1 and Rac1 in the regulation of cell motility and polarity, and propose that similar signaling mechanisms may be of general importance in regulating spatiotemporal dynamics of the actin cytoskeleton by small GTPases. 相似文献
17.
Signaling mechanisms of neurite outgrowth induced by the cell adhesion molecules NCAM and N-Cadherin
Formation of appropriate neural circuits depends on a complex interplay between extracellular guiding cues and intracellular
signaling events that result in alterations of cytoskeletal dynamics and a neurite growth response. Surface-expressed cell
adhesion molecules (CAMs) interact with the surroundings via the extracellular domain and bind to the cytoskeleton via their
intracellular domain. In addition, several CAMs induce signaling events via direct interactions with intracellular proteins
or via interactions with cell surface receptors. Thus, CAMs are obvious candidates for transmitting extracellular guidance
cues to intracellular events and thereby regulating neurite outgrowth. In this review, we focus on two CAMs, the neural cell
adhesion molecule (NCAM) and N-cadherin, and their ability to mediate signaling associated with a neurite outgrowth response.
In particular, we will focus on direct interaction between NCAM and N-cadherin with a number of intracellular partners, as
well as on their interaction with the fibroblast growth factor receptor (FGFR).
Received 23 May 2008; received after revision 14 July 2008; accepted 21 July 2008 相似文献
18.
Sekerková G Zheng L Loomis PA Mugnaini E Bartles JR 《Cellular and molecular life sciences : CMLS》2006,63(19-20):2329-2341
The espins are novel actin-bundling proteins that are produced in multiple isoforms from a single gene. They are present at high concentration in the parallel actin bundle of hair cell stereocilia and are the target of deafness mutations in mice and humans. Espins are also enriched in the microvilli of taste receptor cells, solitary chemoreceptor cells, vomeronasal sensory neurons and Merkel cells, suggesting that espins play important roles in the microvillar projections of vertebrate sensory cells. Espins are potent actin-bundling proteins that are not inhibited by Ca2+. In cells, they efficiently elongate parallel actin bundles and, thereby, help determine the steadystate length of microvilli and stereocilia. Espins bind actin monomer via their WH2 domain and can assemble actin bundles in cells. Certain espin isoforms can also bind phosphatidylinositol 4,5-bisphosphate, profilins or SH3 proteins. These biological activities distinguish espins from other actin-bundling proteins and may make them well-suited to sensory cells. 相似文献
19.
Zhou Y Gunput RA Adolfs Y Pasterkamp RJ 《Cellular and molecular life sciences : CMLS》2011,68(24):4033-4044
MICALs form an evolutionary conserved family of multidomain signal transduction proteins characterized by a flavoprotein monooxygenase
domain. MICALs are being implicated in the regulation of an increasing number of molecular and cellular processes including
cytoskeletal dynamics and intracellular trafficking. Intriguingly, some of these effects are dependent on the MICAL monooxygenase
enzyme and redox signaling, while other functions rely on other parts of the MICAL protein. Recent breakthroughs in our understanding
of MICAL signaling identify the ability of MICALs to bind and directly modify the actin cytoskeleton, link MICALs to the docking
and fusion of exocytotic vesicles, and uncover MICALs as anti-apoptotic proteins. These discoveries could lead to therapeutic
advances in neural regeneration, cancer, and other diseases. 相似文献
20.
Serine proteases exist in eukaryotic and prokaryotic organisms and have emerged during evolution as the most abundant and functionally diverse group. In Gram-negative bacteria, there is a growing family of high molecular weight serine proteases secreted to the external milieu by a fascinating and widely employed bacterial secretion mechanism, known as the autotransporter pathway. They were initially found in Neisseria, Shigella, and pathogenic Escherichia coli, but have now also been identified in Citrobacter rodentium, Salmonella, and Edwardsiella species. Here, we focus on proteins belonging to the serine protease autotransporter of Enterobacteriaceae (SPATEs) family. Recent findings regarding the predilection of serine proteases to host intracellular or extracellular protein-substrates involved in numerous biological functions, such as those implicated in cytoskeleton stability, autophagy or innate and adaptive immunity, have helped provide a better understanding of SPATEs’ contributions in pathogenesis. Here, we discuss their classification, substrate specificity, and potential roles in pathogenesis. 相似文献