Gene/Protein Disease Symptom Drug Enzyme Compound
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The Arabidopsis bypass1 mutant (bps1) exhibits defective shoot and root growth that is associated with constitutive production of a root-derived carotenoid-related signal (Van Norman et al., Curr Biol 14:1739-1746, 2004). Since the identity of the signal and the function of BPS1 are still unknown, we investigated effects of BPS1 depletion in Nicotiana benthamiana to elucidate BPS1 function in plant growth and development. The predicted protein of NbBPS1, a BPS1 homolog of N. benthamiana, contains a central transmembrane domain, and a NbBPS1:GFP fusion protein was mainly associated with the endoplasmic reticulum. Virus-induced gene silencing (VIGS) of NbBPS1 resulted in pleiotrophic phenotypes, including growth retardation and abnormal leaf development. At the cellular level, the plants exhibited hyperproliferation of the cambial cells and defective xylem differentiation during stem vascular development. Hyperactivity of the cambium was associated with an elevated auxin and cytokinin response. In contrast, the leaves had reduced numbers of cells with increased cell size and elevated endoreduplication. Cell death in NbBPS1 VIGS leaves started with vacuole collapse, followed by degeneration of the organelles. Interestingly, these phenotypes were mainly caused by silencing of NbBPS1 in the aerial parts of the plants, different from the case of the Arabidopsis bps1 mutant. These results suggest that NbBPS1 plays a role in the control of cell division and differentiation in the cambium of N. benthamiana, and BPS homologs may have a diverse function in different tissues and in different species.
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PMID:Silencing of a BYPASS1 homolog results in root-independent pleiotrophic developmental defects in Nicotiana benthamiana. 1871 82

A-kinase-anchoring protein 149 (AKAP149) is a membrane protein of the mitochondrial and endoplasmic reticulum/nuclear envelope network. AKAP149 controls the subcellular localization and temporal order of protein phosphorylation by tethering protein kinases and phosphatases to these compartments. AKAP149 also includes an RNA-binding K homology (KH) domain, the loss of function of which has been associated in other proteins with neurodegenerative syndromes. We show here that protein phosphatase 1 (PP1) binding occurs through a conserved RVXF motif found in the KH domain of AKAP149 and that PP1 and RNA binding to this same site is mutually exclusive and controlled through a novel, phosphorylation-dependent mechanism. A collapse of the mitochondrial network is observed upon introduction of RNA-binding deficient mutants of AKAP149, pointing to the importance of RNA tethering to the mitochondrial membrane by AKAP149 for mitochondrial distribution.
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PMID:Mutually exclusive binding of PP1 and RNA to AKAP149 affects the mitochondrial network. 1907 62

ApolipoproteinB (ApoB) is a lipid binding protein that is a nonexchangeable component of chylomicrons, VLDL, and LDL. In the liver and intestinal cells ApoB recruits lipid to form nascent triacylglycerol rich particles cotranslationally in the endoplasmic reticulum membrane which are then processed and secreted to form plasma lipoproteins. The N-terminal domain, which comprises the first 22% of apoB, recruits lipid in a controlled manner. The first 6% (residues 1-291) of the N-terminus does not bind lipid. The first lipid binding domain, including residues 292-782 (B6-17), forms a lipid binding pocket which is predicted to consist of 17 alpha-helices and 6 beta-strands. A structural model based on the X-ray structure of the homologues protein lipovitellin suggests that the N-terminal 6-8 helices and the beta-sheet interact with lipid while the C-terminal helices form a structural unit stabilizing the beta-sheet. Using isothermal drop tensiometry we showed that ApoB6.4-17 is surface active and binds to a triolein/water interface and exerts 16-19 mN/m of pressure (Pi) on that surface. The protein initially adsorbs slowly from aqueous solution to the surface but following compression and re-expansion it reaches equilibrium much faster. When Pi exceeds 16.9 mN/m part of the protein is ejected from the surface, but when compressed to high Pi the protein is never completely ejected indicating that part of the peptide is irreversibly anchored to the interface. The surface dilation modulus (epsilon) varies between 25-38 mN/m, and is predominantly elastic with a small viscous component. When compressed at an air/water interface ApoB6.4-17 has a limiting area of approximately 11 A2 per amino acid at lift off and only approximately 7 A2 per amino acid at the collapse Pi (28 mN/m). These values are about half the anticipated values if all the residues are at the surface. This suggests that ApoB6.4-17 retains some globular structure at an interface and does not completely denature at the surface, as many other globular proteins do. We suggest that while bound to the surface ApoB6.4-17 exhibits properties of both alpha and beta structure giving it unique and versatile characteristics at a hydrophobic interface.
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PMID:Interfacial properties of a complex multi-domain 490 amino acid peptide derived from apolipoprotein B (residues 292-782). 1914 22

Mutations in CLN6 cause variant late-onset neuronal ceroid lipofuscinosis (vLINCL), a childhood neurodegenerative disorder resulting from aberrant neuronal cell loss and pathological accumulation of lysosomal autofluorescent storage material in the central nervous system. The direct function of the endoplasmic reticulum-resident protein CLN6 and how dysfunction of this protein results in vLINCL are unknown. We report that CLN6 interacts with collapsin response mediator protein-2 (CRMP-2). To further understand the significance and possible contribution to vLINCL of the CLN6-CRMP-2 interaction, we utilized the nclf mouse, which harbors mutations in CLN6. Significantly, CRMP-2 protein level was found to be reduced in the nclf mouse brain, particularly in the thalamus. Because CRMP-2 functions in growth cone collapse and is an effector protein downstream of Sema3A signaling, this pathway was examined via a dorsal root ganglion (DRG) repulsion assay. However, there were no defects in the repulsion of DRGs derived from nclf mice, indicating that the loss of CLN6 does not affect Sema3A signaling. CRMP-2 has also been implicated in controlling axon number and outgrowth, as observed in cultured hippocampal neurons. Therefore, we explored the formation and maturation of hippocampal neurons derived from nclf mice in a glial coculture system. The maturation of these neurons was reduced; by day in vitro (DIV) 8, more than 50% of nclf-derived hippocampal neurons had died. Additionally, beginning around DIV4, nclf neurons were less mature than their WT counterparts, presumably because of an inability to form mature synaptic connections. We concluded that alterations in neurite maturation resulting from a loss of CLN6-CRMP-2 interaction may contribute to neuronal dysfunction and pathology in vLINCL.
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PMID:Protein product of CLN6 gene responsible for variant late-onset infantile neuronal ceroid lipofuscinosis interacts with CRMP-2. 1923 93

In addition to its ability to accelerate filament assembly, which is common to formins, INF2 is a formin protein with the unique biochemical ability to accelerate actin filament depolymerization. The depolymerization activity of INF2 requires its actin monomer-binding WASP homology 2 (WH2) motif. In this study, we show that INF2 is peripherally bound to the cytoplasmic face of the endoplasmic reticulum (ER) in Swiss 3T3 cells. Both endogenous INF2 and GFP-fusion constructs display ER localization. INF2 is post-translationally modified by a C-terminal farnesyl group, and this modification is required for ER interaction. However, farnesylation is not sufficient for ER association, and membrane extraction experiments suggest that ionic interactions are also important. The WH2 motif also serves as a diaphanous autoregulatory domain (DAD), which binds to the N-terminal diaphanous inhibitory domain (DID), with an apparent dissociation constant of 1.1 muM. Surprisingly, the DID-DAD interaction does not inhibit the actin nucleation activity of INF2; however, it does inhibit the depolymerization activity. Point mutations to the DAD/WH2 inhibit both the DID-DAD interaction and depolymerization activity. Expression of GFP-INF2 containing these DAD/WH2 mutations causes the ER to collapse around the nucleus, with accumulation of actin filaments around the collapsed ER. This study is the first to show the association of an actin-assembly factor with the ER.
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PMID:INF2 is an endoplasmic reticulum-associated formin protein. 1936 33

The endoplasmic reticulum (ER) is a dynamic multifunction organelle that is responsible for Ca(2+) homeostasis, protein folding, post-translational modification, protein degradation, and transportation of nascent proteins. Disruption of ER architecture might affect the normal physiology of the cell. In yeast, expansion of the ER is observed under unfolded protein response (UPR) and subsequently induces autophagy initiated from the ER. Here, we found that soluble low molecular weight of Abeta disrupted the anchoring between ER and microtubules (MT) and induced collapse of ER. In addition, it decreased the stability of MT. Subsequently, low molecular weight Abeta triggered autophagy and enhanced lysosomal degradation, as shown by electron microscopy and live-cell imaging. Dysfunction of ER can be further proved in postmortem AD brain and transgenic mice bearing APP Swedish mutation by immunohistochemical analysis of calreticulin. Treatment with Taxol, a MT-stabilizing agent, could partially inhibit collapse of the ER and induction of autophagy. The results show that Abeta-induced disruption of MT can affect the architecture of the ER. Collapse/aggregation of the ER may play an important role in Abeta peptide-triggered neurodegenerative processes.
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PMID:Low molecular weight Abeta induces collapse of endoplasmic reticulum. 1938 29

Ceramides are central intermediates of sphingolipid metabolism with critical functions in cell organization and survival. They are synthesized on the cytosolic surface of the endoplasmic reticulum (ER) and transported by ceramide transfer protein to the Golgi for conversion to sphingomyelin (SM) by SM synthase SMS1. In this study, we report the identification of an SMS1-related (SMSr) enzyme, which catalyses the synthesis of the SM analogue ceramide phosphoethanolamine (CPE) in the ER lumen. Strikingly, SMSr produces only trace amounts of CPE, i.e., 300-fold less than SMS1-derived SM. Nevertheless, blocking its catalytic activity causes a substantial rise in ER ceramide levels and a structural collapse of the early secretory pathway. We find that the latter phenotype is not caused by depletion of CPE but rather a consequence of ceramide accumulation in the ER. Our results establish SMSr as a key regulator of ceramide homeostasis that seems to operate as a sensor rather than a converter of ceramides in the ER.
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PMID:Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER. 1950 37

The textbook image of the plant vacuole sitting passively in the centre of the cell is not always correct. We observed vacuole dynamics in the epidermal cells of red onion (Allium cepa) bulbs, using confocal microscopy to detect autofluorescence from the pigment anthocyanin. The central vacuole was penetrated by highly mobile transvacuolar strands of cytoplasm, which were also visible in concurrent transmitted light images. Tubular vacuoles also extended from the large central vacuole and radiated through the cortical cytoplasm. These tubules were thin, having a diameter of about 1.5 microm, and were connected to the central vacuole as shown by fluorescence recovery after photobleaching (FRAP) experiments. The tubules were bounded by the tonoplast, as revealed by transient expression of green fluorescent protein (GFP) targeted to the vacuolar membrane and through labeling with the dye MDY-64. Expression of endoplasmic reticulum-targeted GFP demonstrated that the vacuolar tubules were distinct from the cortical endoplasmic reticulum. Movement of the tubular vacuoles depended on actin microfilaments, as microfilament disruption blocked tubule movement and caused their collapse into minivacuoles. The close association of the tubules with GFP-tagged actin microfilaments suggests that the tubules are associated with myosin, and that tubules likely move along microfilaments. Tubular vacuoles do not require anthocyanin for their formation, as tubules were also present in white onion cells that lack anthocyanin. The function of these tubular vacuoles remains unknown, but as they greatly increase the surface area of the tonoplast, they might increase transport rates between the cytoplasm and vacuole.
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PMID:New dynamics in an old friend: dynamic tubular vacuoles radiate through the cortical cytoplasm of red onion epidermal cells. 1976 37

The purpose of the study was to explore the ultrastructural alterations of adult Schistosoma japonicum induced by mefloquine. Eight out of ten mice infected with 60-80 S. japonuicum cercariae for 35 days were treated orally with mefloquine at a single dose of 400 mg/kg. Four groups of two mice were killed at 8 h, 24 h, 3 days, and 7 days post-treatment, and schistosomes were collected by perfusion technique, fixed, and examined under a transmission electron microscope. Schistosomes obtained from the remaining two mice served as control. Eight hours after mefloquine 400 mg/kg was administered to the infected mice, various alterations in the tegument and subtegument tissues of both male and female worms were seen, which included focal lysis of tegmental matrix resulted in vacuole formation, decrease in rod-like and discoid-like secretary bodies, light swelling or focal lysis of musculature, extensive lysis of internal structure of sensory organelles, and appearance of vacuole or myelin-like structure in perinuclear cytoplasm of syncytium and epithelial cells. In vitelline cells of female worms, the most significant alteration was extensive lysis or fusion of vitelline balls in vitelline droplets and decrease in granular endoplasmic reticulum Twenty-four hours post-treatment, damage to the tegument and subtegument tissues had increased in severity. In male worms, the most prominent alterations were emergence of large vacuoles in the tegument, detachment of cytoplasmic process from the tegumental surface, focal collapse of internal structure of sensory organelle, and loss of definition of syncytium and gut epithelial cell. In female worms, focal lysis in tegumental matrix, musculature, and parenchymal tissues resulted in emergence of vacuole or myelin-like structure, reduction of nucleoli, fusion of partial nuclear membrane together with cytoplasm in epithelial cell, and lysis of interstitial tissues among the vitelline cells which were universal. Three and 7 days post-treatment, besides the aforementioned alterations, the significant damage to the male worms were disrupted outer plasma membrane detached from the cytoplasmic process, swelling of individual cytoplasmic process, extensive swelling and focal lysis in the musculature, parenchymal tissues and perinuclear cytoplasm of syncytium, accompanied by emergence of swollen mitochondria, vacuoles, and myelin-like structure, and severe damage to gut epithelial cell. In female worms, apart from disruption of outer plasmic membrane in cytoplasmic process, severe swelling of tegumental matrix accompanied by emergence of vacuoles, swollen mitochondria and myelin-like structure, focal lysis of heterochromatin and nucleoli, disappearance of microvilli in gut epithelial cells, and emergence of myelin-like structures in vitelline cells were observed. The results indicate that administration of mefloquine to mice infected with adult S. japonicum exhibits an extensive damage to the ultrastructure in tegument and subtegument tissues including syncytium, gut epithelial cells, parenchymal tissues, and vitelline cells of schistosomes.
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PMID:Transmission electron microscopic observation on ultrastructural alterations in Schistosoma japonicum caused by mefloquine. 2017 26

Secretory proteins are exported from the endoplasmic reticulum (ER) at specialized regions known as the transitional ER (tER). Coat protein complex II (COPII) proteins are enriched at tER sites, although the mechanisms underlying tER site assembly and maintenance are not understood. Here, we investigated the dynamic properties of tER sites in Saccharomyces cerevisiae and probed protein and lipid requirements for tER site structure and function. Thermosensitive sec12 and sec16 mutations caused a collapse of tER sites in a manner that depended on nascent secretory cargo. Continual fatty acid synthesis was required for ER export and for normal tER site structure, whereas inhibition of sterol and ceramide synthesis produced minor effects. An in vitro assay to monitor assembly of Sec23p-green fluorescent protein at tER sites was established to directly test requirements. tER sites remained active for approximately 10 min in vitro and depended on Sec12p function. Bulk phospholipids were also required for tER site structure and function in vitro, whereas depletion of phophatidylinositol selectively inhibited coat protein complex II (COPII) budding but not assembly of tER site structures. These results indicate that tER sites persist through relatively stringent treatments in which COPII budding was strongly inhibited. We propose that tER site structures are stable elements that are assembled on an underlying protein and lipid scaffold.
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PMID:Requirements for transitional endoplasmic reticulum site structure and function in Saccharomyces cerevisiae. 2020 Feb 24


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