共查询到20条相似文献,搜索用时 46 毫秒
1.
Simone Eggert A. C. Gonzalez C. Thomas S. Schilling S. M. Schwarz C. Tischer V. Adam P. Strecker V. Schmidt T. E. Willnow G. Hermey C. U. Pietrzik E. H. Koo Stefan Kins 《Cellular and molecular life sciences : CMLS》2018,75(2):301-322
Proteolytic cleavage of the amyloid precursor protein (APP) by α-, β- and γ-secretases is a determining factor in Alzheimer’s disease (AD). Imbalances in the activity of all three enzymes can result in alterations towards pathogenic Aβ production. Proteolysis of APP is strongly linked to its subcellular localization as the secretases involved are distributed in different cellular compartments. APP has been shown to dimerize in cis-orientation, affecting Aβ production. This might be explained by different substrate properties defined by the APP oligomerization state or alternatively by altered APP monomer/dimer localization. We investigated the latter hypothesis using two different APP dimerization systems in HeLa cells. Dimerization caused a decreased localization of APP to the Golgi and at the plasma membrane, whereas the levels in the ER and in endosomes were increased. Furthermore, we observed via live cell imaging and biochemical analyses that APP dimerization affects its interaction with LRP1 and SorLA, suggesting that APP dimerization modulates its interplay with sorting molecules and in turn its localization and processing. Thus, pharmacological approaches targeting APP oligomerization properties might open novel strategies for treatment of AD. 相似文献
2.
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
3.
J. K. Walter V. Castro M. Voss K. Gast C. Rueckert J. Piontek Ingolf E. Blasig 《Cellular and molecular life sciences : CMLS》2009,66(22):3655-3662
Occludin is a self-associating transmembrane tight junction protein affected in oxidative stress. However, its function is
unknown. The cytosolic C-terminal tail contains a coiled coil-domain forming dimers contributing to the self-association.
Studying the hypothesis that the self-association is redox-sensitive, we found that the dimerization of the domain depended
on the sulfhydryl concentration of the environment in low-millimolar range. Under physiological conditions, monomers and dimers
were detected. Masking the sulfhydryl residues in the domain prevented the dimerization but affected neither its helical structure
nor cylindric shape. Incubation of cell extracts containing full-length occludin with sulfhydryl reagents prevented the dimerization;
a cysteine/alanine exchange mutant also did not show dimer formation. This demonstrates, for the first time, that disulfide
bridge formation of the domain is involved in the occludin dimerization. It is concluded that the redox-dependent dimerization
of occludin may play a regulatory role in the tight junction assembly under physiological and pathological conditions. 相似文献
4.
Yuan Pan Joseph G. Laird David M. Yamaguchi Sheila A. Baker 《Cellular and molecular life sciences : CMLS》2015,72(4):833-843
Hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels carry Ih, which contributes to neuronal excitability and signal transmission in the nervous system. Controlling the trafficking of HCN1 is an important aspect of its regulation, yet the details of this process are poorly understood. Here, we investigated how the C-terminus of HCN1 regulates trafficking by testing for its ability to redirect the localization of a non-targeted reporter in transgenic Xenopus laevis photoreceptors. We found that HCN1 contains an ER localization signal and through a series of deletion constructs, identified the responsible di-arginine ER retention signal. This signal is located in the intrinsically disordered region of the C-terminus of HCN1. To test the function of the ER retention signal in intact channels, we expressed wild type and mutant HCN1 in HEK293 cells and found this signal negatively regulates surface expression of HCN1. In summary, we report a new mode of regulating HCN1 trafficking: through the use of a di-arginine ER retention signal that monitors processing of the channel in the early secretory pathway. 相似文献
5.
E. Carafoli E. Garcia-Martin D. Guerini 《Cellular and molecular life sciences : CMLS》1996,52(12):1091-1100
The Ca2+ pump of the plasma membrane (PMCA) is regulated by a number of agents. The most important is calmodulin (CaM), which binds to a domain located in the C-terminal portion of the pump, removing it from an autoinhibitory site next to the active site. The CaM-binding domain is preceded by an acidic sequence which contains a hidden signal for endoplasmic reticulum (ER) retention. Chimeras of the PMCA and endoplasmic reticulum (SERCA) pumps have revealed the presence of a strong signal for ER retention in the first 45 residues of the SERCA pump. Four gene products of the PMCA pump are known: two of them (1 and 4) are ubiquitously expressed, two (2 and 3) are specific for nerve cells and may be induced by their activation. Mutagenesis work has identified four residues in three of the transmembrane domains of the pump which may be components of the trans-protein Ca2+ path. The mutation of two of these residues alters the membrane targeting of the pump. 相似文献
6.
Kristin T. Jacobsen Kerstin Iverfeldt 《Cellular and molecular life sciences : CMLS》2009,66(14):2299-2318
The Alzheimer’s amyloid precursor protein (APP) belongs to a conserved gene family that also includes the mammalian APLP1
and APLP2, the Drosophila APPL, and the C. elegans APL-1. The biological function of APP is still not fully clear. However, it is known that the APP family proteins have redundant
and partly overlapping functions, which demonstrates the importance of studying all APP family members to gain a more complete
picture. When APP was first cloned, it was speculated that it could function as a receptor. This theory has been further substantiated
by studies showing that APP and its homologues bind both extracellular ligands and intracellular adaptor proteins. The APP
family proteins undergo regulated intramembrane proteolysis (RIP), generating secreted and cytoplasmic fragments that have
been ascribed different functions. In this review, we will discuss the APP family with focus on biological functions, binding
partners, and regulated processing. 相似文献
7.
Karine Laulagnier Charlotte Javalet Fiona J. Hemming Mathilde Chivet Gaëlle Lachenal Béatrice Blot Christine Chatellard Rémy Sadoul 《Cellular and molecular life sciences : CMLS》2018,75(4):757-773
Amyloid beta peptide (Aβ), the main component of senile plaques of Alzheimer’s disease brains, is produced by sequential cleavage of amyloid precursor protein (APP) and of its C-terminal fragments (CTFs). An unanswered question is how amyloidogenic peptides spread throughout the brain during the course of the disease. Here, we show that small lipid vesicles called exosomes, secreted in the extracellular milieu by cortical neurons, carry endogenous APP and are strikingly enriched in CTF-α and the newly characterized CTF-η. Exosomes from N2a cells expressing human APP with the autosomal dominant Swedish mutation contain Aβ peptides as well as CTF-α and CTF-η, while those from cells expressing the non-mutated form of APP only contain CTF-α and CTF-η. APP and CTFs are sorted into a subset of exosomes which lack the tetraspanin CD63 and specifically bind to dendrites of neurons, unlike exosomes carrying CD63 which bind to both neurons and glial cells. Thus, neuroblastoma cells secrete distinct populations of exosomes carrying different cargoes and targeting specific cell types. APP-carrying exosomes can be endocytosed by receiving cells, allowing the processing of APP acquired by exosomes to give rise to the APP intracellular domain (AICD). Thus, our results show for the first time that neuronal exosomes may indeed act as vehicles for the intercellular transport of APP and its catabolites. 相似文献
8.
Golgi-endomannosidase provides an alternate glucosidase-independent pathway of glucose trimming. Activity for endomannosidase
is detectable in various tissues and cell lines but not in CHO cells. Cloning of CHO cell endomannosidase revealed that the
highly conserved Trp188 and Arg177 of vertebrate endomannosidase were both substituted by Cys. The Trp188Cys substitution
was functionally important since it alone resulted in endoplasmic reticulum (ER) mislocalization of endomannosidase and caused
the greatly reduced in vivo activity. These effects could be reversed in cells with a back-engineered Cys188Trp CHO cell endomannosidase, in particular
N-glycans of α1-antitrypsin became fully processed. The intramolecular disulfide bridge of CHO cell endomannosidase formed
with the additional Cys188 was not solely responsible for the reduced enzyme activity since endomannosidase with engineered
Cys188Ala or Ser substitutions did not restore enzyme activity and was ER mislocalized. Thus, the conserved Trp188 residue
in endomannosidases is of critical importance for correct subcellular localization and in vivo activity of the enzyme.
Received 7 May 2007; received after revision 31 May 2007; accepted 11 June 2007 相似文献
9.
Tubulin chaperone E binds microtubules and proteasomes and protects against misfolded protein stress
Olga Voloshin Yana Gocheva Marina Gutnick Natalia Movshovich Anya Bakhrat Keren Baranes-Bachar Dudy Bar-Zvi Ruti Parvari Larisa Gheber Dina Raveh 《Cellular and molecular life sciences : CMLS》2010,67(12):2025-2038
Mutation of tubulin chaperone E (TBCE) underlies hypoparathyroidism, retardation, and dysmorphism (HRD) syndrome with defective
microtubule (MT) cytoskeleton. TBCE/yeast Pac2 comprises CAP-Gly, LRR (leucine-rich region), and UbL (ubiquitin-like) domains.
TBCE folds α-tubulin and promotes α/β dimerization. We show that Pac2 functions in MT dynamics: the CAP-Gly domain binds α-tubulin
and MTs, and functions in suppression of benomyl sensitivity of pac2Δ mutants. Pac2 binds proteasomes: the LRR binds Rpn1, and the UbL binds Rpn10; the latter interaction mediates Pac2 turnover.
The UbL also binds the Skp1-Cdc53-F-box (SCF) ubiquitin ligase complex; these competing interactions for the UbL may impact
on MT dynamics. pac2Δ mutants are sensitive to misfolded protein stress. This is suppressed by ectopic PAC2 with both the CAP-Gly and UbL domains being essential. We propose a novel role for Pac2 in the misfolded protein stress response
based on its ability to interact with both the MT cytoskeleton and the proteasomes. 相似文献
10.
Hulpke S Tomioka M Kremmer E Ueda K Abele R Tampé R 《Cellular and molecular life sciences : CMLS》2012,69(19):3317-3327
The loading of antigenic peptides onto major histocompatibility complex class I (MHC I) molecules is an essential step in the adaptive immune response against virally or malignantly transformed cells. The ER-resident peptide-loading complex (PLC) consists of the transporter associated with antigen processing (TAP1 and TAP2), assembled with the auxiliary factors tapasin and MHC I. Here, we demonstrated that the N-terminal extension of each TAP subunit represents an autonomous domain, named TMD(0), which is correctly targeted to and inserted into the ER membrane. In the absence of coreTAP, each TMD(0) recruits tapasin in a 1:1 stoichiometry. Although the TMD(0)s lack known ER retention/retrieval signals, they are localized to the ER membrane even in tapasin-deficient cells. We conclude that the TMD(0)s of TAP form autonomous interaction hubs linking antigen translocation into the ER with peptide loading onto MHC I, hence ensuring a major function in the integrity of the antigen-processing machinery. 相似文献
11.
Valerie Le Fourn Sujin Park Insook Jang Katarina Gaplovska-Kysela Bruno Guhl Yangsin Lee Jin Won Cho Christian Zuber Jürgen Roth 《Cellular and molecular life sciences : CMLS》2013,70(11):1985-2002
Multisubunit protein complexes are assembled in the endoplasmic reticulum (ER). Existing pools of single subunits and assembly intermediates ensure the efficient and rapid formation of complete complexes. While being kinetically beneficial, surplus components must be eliminated to prevent potentially harmful accumulation in the ER. Surplus single chains are cleared by the ubiquitin–proteasome system. However, the fate of not secreted assembly intermediates of multisubunit proteins remains elusive. Here we show by high-resolution double-label confocal immunofluorescence and immunogold electron microscopy that naturally occurring surplus fibrinogen Aα–γ assembly intermediates in HepG2 cells are dislocated together with EDEM1 from the ER to the cytoplasm in ER-derived vesicles not corresponding to COPII-coated vesicles originating from the transitional ER. This route corresponds to the novel ER exit path we have previously identified for EDEM1 (Zuber et al. Proc Natl Acad Sci USA 104:4407–4412, 2007). In the cytoplasm, detergent-insoluble aggregates of fibrinogen Aα–γ dimers develop that are targeted by the selective autophagy cargo receptors p62/SQSTM1 and NBR1. These aggregates are degraded by selective autophagy as directly demonstrated by high-resolution microscopy as well as biochemical analysis and inhibition of autophagy by siRNA and kinase inhibitors. Our findings demonstrate that different pathways exist in parallel for ER-to-cytoplasm dislocation and subsequent proteolytic degradation of large luminal protein complexes and of surplus luminal single-chain proteins. This implies that ER-associated protein degradation (ERAD) has a broader function in ER proteostasis and is not limited to the elimination of misfolded glycoproteins. 相似文献
12.
Thilo Bartolm?s Caroline Hirschfeld-Ihlow Sven Jonas Michael Schaefer Reinhard Ge?ner 《Cellular and molecular life sciences : CMLS》2012,69(22):3851-3862
LI-cadherin belongs to the family of 7D-cadherins that is characterized by a low sequence similarity to classical cadherins, seven extracellular cadherin repeats (ECs), and a short cytoplasmic domain. Nevertheless, LI-cadherins mediates Ca2+-dependent cell–cell adhesion and induces an epitheloid cellular phenotype in non-polarized CHO cells. Whereas several studies suggest that classical cadherins cis-dimerize in a Ca2+-dependent manner and interact in trans by strand-swapping tryptophan 2 of EC1, little is known about the molecular interactions of LI-cadherin, which lacks tryptophan 2. We thus expressed fluorescent LI-cadherin fusion proteins in HEK293 and CHO cells, analyzed their cell–cell adhesive properties and studied their cellular distribution, cis-interaction, and lateral diffusion in the presence and absence of Ca2+. LI-cadherin highly concentrates in cell contact areas but rapidly leaves those sites upon Ca2+ depletion and redistributes evenly on the cell surface, indicating that it is only kept in the contact areas by trans-interactions. Fluorescence resonance energy transfer analysis of LI-cadherin-CFP and -YFP revealed that LI-cadherin forms cis-dimers that resist Ca2+ depletion. As determined by fluorescence redistribution after photobleaching, LI-cadherin freely diffuses in the plasma membrane as a cis-dimer (D?=?0.42?±?0.03?μm2/s). When trapped by trans-binding in cell contact areas, its diffusion coefficient decreases only threefold to D?=?0.12?±?0.01?μm2/s, revealing that, in contrast to classical and desmosomal cadherins, trans-contacts formed by LI-cadherin are highly dynamic. 相似文献
13.
J. Mihaly I. Hogga S. Barges M. Galloni R. K. Mishra K. Hagstrom M. Müller P. Schedl L. Sipos J. Gausz H. Gyurkovics F. Karch 《Cellular and molecular life sciences : CMLS》1998,54(1):60-70
Eukaryotic chromosomes are thought to be organized into a series of discrete higher-order chromatin domains. This organization
is believed to be important not only in the compaction of the chromatin fibre, but also in the utilization of genetic information.
Critical to this model are the domain boundaries that delimit and segregate the chromosomes into units of independent gene
activity. In Drosophila, such domain boundaries have been identified through two different approaches. On the one hand, elements like scs/scs′ and
the reiterated binding site for the SU(HW) protein have been characterized through their activity of impeding enhancer-promoter
interactions when intercalated between them. Their role of chromatin insulators can protect transgenes from genomic position
effects, thereby establishing in dependent functional domains within the chromosome. On the other hand, domain boundaries
of the Bithorax complex (BX-C) like Fab-7 and Mcp have been identified through mutational analysis. Mcp and Fab-7, however, may represent a specific class of boundary elements; instead of separating adjacent domains that contain separate
structural genes, Mcp and Fab-7 delimit adjacent cis-regulatory domains, each of which interacts independently with their target promoters. In this article, we review the genetic
and molecular characteristics of the domain boundaries of the BX-C. We describe how Fab-7 functions to confine activating as well as repressive signals to the flanking regulatory domains. Although the mechanisms
by which Fab-7 works as a domain boundary remain an open issue, we provide preliminary evidence that Fab-7 is not a mere insulator like scs or the reiterated binding site for the SU(HW) protein. 相似文献
14.
D. E. Dye S. Karlen B. Rohrbach O. Staub L. R. Braathen K. A. Eidne D. R. Coombe 《Cellular and molecular life sciences : CMLS》2009,66(4):681-696
hShroom1 (hShrm1) is a member of the Apx/Shroom (Shrm) protein family and was identified from a yeast two-hybrid screen as
a protein that interacts with the cytoplasmic domain of melanoma cell adhesion molecule (MCAM). The characteristic signature
of the Shrm family is the presence of a unique domain, ASD2 (Apx/Shroom domain 2). mRNA analysis suggests that hShrm1 is expressed
in brain, heart, skeletal muscle, colon, small intestine, kidney, placenta and lung tissue, as well a variety of melanoma
and other cell lines. Co-immunoprecipitation and bioluminescence resonance energy transfer (BRET) experiments indicate that
hShrm1 and MCAM interact in vivo and by immunofluorescence microscopy some co-localization of these proteins is observed. hShrm1 partly co-localises with
β-actin and is found in the Triton X-100 insoluble fraction of melanoma cell extracts. We propose that hShrm1 is involved
in linking MCAM to the cytoskeleton.
D. E. Dye, S. Karlen: These authors contributed equally to this work.
Received 09 October 2008; received after revision 23 November 2008; accepted 09 December 2008 相似文献
15.
This review presents plant-specific characteristics of the Golgi apparatus and discusses their impact on retention of membrane proteins in the Golgi or the trans-Golgi network (TGN). The plant Golgi consists of distinct stacks of cisternae that actively move throughout the cytoplasm. The Golgi apparatus is a very dynamic compartment and the site for maturation of N-linked glycans. It is also a factory for complex carbohydrates that are part of the cell wall. The TGN is believed to be the site from where vacuolar proteins are sorted by receptors towards each type of vacuole. To maintain the structure and specific features of the Golgi, resident proteins ought to be maintained in the proper Golgi cisternae or in the TGN. Two families of membrane proteins will be taken as examples for Golgi/TGN retention: (i) the enzymes involved in N-glycosylation processes and (ii) a vacuolar sorting receptor. Although the number of available plant proteins localized in Golgi/TGN is low, the basis of retention appears to be shared over all kingdoms and may result from pure retention and recycling mechanisms. In this review, we will summarize the characteristics of a plant Golgi and will discuss especially their consequences on on the study of this highly dynamic structure. We then choose membrane proteins with a single transmembrane domain to illustrate the signals and mechanisms involved in plants to localize and maintain proteins in the Golgi and the TGN. 相似文献
16.
Poelarends GJ Veetil VP Whitman CP 《Cellular and molecular life sciences : CMLS》2008,65(22):3606-3618
Tautomerase superfamily members have an amino-terminal proline and a β–α–β fold, and include 4-oxalocrotonate tautomerase
(4-OT), 5-(carboxymethyl)-2-hydroxymuconate isomerase (CHMI), trans- and cis-3-chloroacrylic acid dehalogenase (CaaD and cis-CaaD, respectively), malonate semialdehyde decarboxylase (MSAD), and macrophage migration inhibitory factor (MIF), which
exhibits a phenylpyruvate tautomerase (PPT) activity. Pro-1 is a base (4-OT, CHMI, the PPT activity of MIF) or an acid (CaaD,
cis-CaaD, MSAD). Components of the catalytic machinery have been identified and mechanistic hypotheses formulated. Characterization
of new homologues shows that these mechanisms are incomplete. 4-OT, CaaD, cis-CaaD, and MSAD also have promiscuous activities with a hydratase activity in CaaD, cis-CaaD, and MSAD, PPT activity in CaaD and cis-CaaD, and CaaD and cis-CaaD activities in 4-OT. The shared promiscuous activities provide evidence for divergent evolution from a common ancestor,
give hints about mechanistic relationships, and implicate catalytic promiscuity in the emergence of new enzymes.
Received 22 May 2008; received after revision 20 June 2008; accepted 02 July 2008 相似文献
17.
Matthias Samereier Otto Baumann Irene Meyer Ralph Gräf 《Cellular and molecular life sciences : CMLS》2011,68(2):275-287
We have localized TACC to the microtubule-nucleating centrosomal corona and to microtubule plus ends. Using RNAi we proved
that Dictyostelium TACC promotes microtubule growth during interphase and mitosis. For the first time we show in vivo that both TACC and XMAP215
family proteins can be differentially localized to microtubule plus ends during interphase and mitosis and that TACC is mainly
required for recruitment of an XMAP215-family protein to interphase microtubule plus ends but not for recruitment to centrosomes
and kinetochores. Moreover, we have now a marker to study dynamics and behavior of microtubule plus ends in living Dictyostelium cells. In a combination of live cell imaging of microtubule plus ends and fluorescence recovery after photobleaching (FRAP)
experiments of GFP-α-tubulin cells we show that Dictyostelium microtubules are dynamic only in the cell periphery, while they remain stable at the centrosome, which also appears to harbor
a dynamic pool of tubulin dimers. 相似文献
18.
Sabine Gröbner Evelyn Fritz Friederike Schoch Martin Schaller Alexander C. Berger Michael Bitzer Ingo B. Autenrieth 《Cellular and molecular life sciences : CMLS》2010,67(19):3331-3344
Enterococci are commensal organisms in the alimentary tract. However, they can cause a variety of life-threatening infections,
especially in nosocomial settings. We hypothesized that induction of cell death might enable these facultative pathogenic
bacteria to evade the innate immune response and to cause infections of their host. We demonstrate that E. faecium when exposed to lysozyme induces cell death in macrophages in vitro and in vivo. Flow cytometric analyses of J774A.1 macrophages
infected with E. faecium revealed loss of cell membrane integrity indicated by uptake of propidium iodide and decrease of the inner mitochondrial
transmembrane potential ΔΨm. Inhibition of caspases, treatment of macrophages with cytochalasin D, or rifampicin did not prevent cells from dying, suggesting
cell death mechanisms that are independent of caspase activation, bacterial uptake, and intracellular bacterial replication.
Characteristics of necrotic cell death were demonstrated by both lack of procaspase 3 activation and cell shrinkage, electron
microscopy, and release of lactate dehydrogenase. Pretreatment of E. faecium with lysozyme and subsequently with broad spectrum protease considerably reduced cell death, suggesting that a bacterial
surface protein is causative for cell death induction. Moreover, in a mouse peritonitis model we demonstrated that E. faecium induces cell death of peritoneal macrophages in vivo. Altogether, our results show that enterococci, under specific conditions
such as exposure to lysozyme, induce necrotic cell death in macrophages, which might contribute to disseminated infections
by these facultative pathogenic bacteria. 相似文献
19.
Summary The synthesis ofcis-erythro- andcis-threo-1, 3-dihydroxy-2-amino-4-octadecene, two further stereoisomers of sphingosine, is described. 相似文献
20.
Eukaryotic genomes have complex spatial organization in the nucleus. The factors and the mechanisms involved in this organization
remain an enigma. Among the many proteins implicated in such a role, the ubiquitous Zn-finger protein CTCF stands out. Here
we summarize the evidence placing CTCF in the enviable position of a master organizer of the genome. CTCF can form loops in cis, and can bridge sequences located on different chromosomes in trans. The thousands of CTCF binding sites, identified in recent genome-wide localization studies, and their distribution along
the genome further support a crucial role of CTCF as a chromatin organizer.
Received 10 October 2008; received after revision 11 December 2008; accepted 16 December 2008 相似文献