Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q07644 (polypeptide)
 72,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

alpha-Latrotoxin is a presynaptic neurotoxin isolated from the venom of the black widow spider Latrodectus tredecimguttatus. It exerts toxic effects in the vertebrate central nervous system by depolarizing neurons, by increasing [Ca2+]i and by stimulating uncontrolled exocytosis of neurotransmitters from nerve terminals. The actions of alpha-latrotoxin are mediated, in part, by a GTP-binding protein-coupled receptor referred to as CIRL or latrophilin. Exendin-4 is also a venom toxin, and it is derived from the salivary gland of the Gila monster Heloderma suspectum. It acts as an agonist at the receptor for glucagon-like peptide-1(7-36)-amide (GLP-1), thereby stimulating secretion of insulin from pancreatic beta-cells of the islets of Langerhans. Here is reported a surprising structural homology between alpha-latrotoxin and exendin-4 that is also apparent amongst all members of the GLP-1-like family of secretagogic hormones (GLP-1, glucagon, vasoactive intestinal polypeptide, secretin, pituitary adenylyl cyclase activating polypeptide). On the basis of this homology, we report the synthesis and initial characterization of a chimeric peptide (Black Widow GLP-1) that stimulates Ca2+ signaling and insulin secretion in human beta-cells and MIN6 insulinoma cells. It is also reported here that the GTP-binding protein-coupled receptors for alpha-latrotoxin and exendin-4 share highly significant structural similarity in their extracellularly-oriented amino-termini. We propose that molecular mimicry has generated conserved structural motifs in secretagogic toxins and their receptors, thereby explaining the evolution of defense or predatory strategies that are shared in common amongst distantly related species including spiders, lizards, and snakes. Evidently, the toxic effects of alpha-latrotoxin and exendin-4 are explained by their ability to interact with GTP-binding protein-coupled receptors that normally mediate the actions of endogenous hormones or neuropeptides.
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PMID:Black widow spider alpha-latrotoxin: a presynaptic neurotoxin that shares structural homology with the glucagon-like peptide-1 family of insulin secretagogic hormones. 997 93

Parathyroid hormone-related protein (PTHrP), expressed in a range of tumors, has endocrine, autocrine/paracrine, and intracrine actions, some of which relate to its ability to localize in the nucleus. Here we show for the first time that extracellularly added human PTHrP (amino acids 1-108) can be taken up specifically by receptor-expressing UMR106.01 osteogenic sarcoma cells and accumulate to quite high levels in the nucleus and nucleolus within 40 min. Quantitation of recognition by the nuclear localization sequence (NLS)-binding importin subunits indicated that in contrast to proteins containing conventional NLSs, PTHrP is recognized exclusively by importin beta and not by importin alpha. The sequence of PTHrP responsible for binding was mapped to amino acids 66-94, which includes an SV40 large tumor-antigen NLS-like sequence, although sequence determinants amino-terminal to this region were also necessary for high affinity binding (apparent dissociation constant of approximately 2 nM for importin beta). Nuclear import of PTHrP was assessed in vitro using purified components, demonstrating that importin beta, together with the GTP-binding protein Ran, was able to mediate efficient nuclear accumulation in the absence of importin alpha, whereas the addition of nuclear transport factor NTF2 reduced transport. The polypeptide ligand PTHrP thus appears to be accumulated in the nucleus/nucleolus through a novel, NLS-dependent nuclear import pathway independent of importin alpha and perhaps also of NTF2.
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PMID:Importin beta recognizes parathyroid hormone-related protein with high affinity and mediates its nuclear import in the absence of importin alpha. 1006 3

The mammalian GTP-binding protein GSPT, whose carboxyl-terminal sequence is homologous to the eukaryotic elongation factor EF1alpha, binds to the polypeptide chain releasing factor eRF1 to function as eRF3 in the translation termination. The amino-terminal domain of GSPT was, however, not required for the binding. Search for other GSPT-binding proteins in yeast two-hybrid screening system resulted in the identification of a cDNA encoding polyadenylate-binding protein (PABP), whose amino terminus is associating with the poly(A) tail of mRNAs presumably for their stabilization. The interaction appeared to be mediated through the carboxyl-terminal domain of PABP and the amino-terminal region of GSPT. Interestingly, multimerization of PABP with poly(A), which is ascribed to the action of its carboxyl-terminal domain, was completely inhibited by the interaction with the amino-terminal domain of GSPT. These results indicate that GSPT/eRF3 may play important roles not only in the termination of protein synthesis but also in the regulation of mRNA stability. Thus, the present study is the first report showing that GSPT/eRF3 carries the translation termination signal to 3'-poly(A) tail ubiquitously present in eukaryotic mRNAs.
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PMID:The eukaryotic polypeptide chain releasing factor (eRF3/GSPT) carrying the translation termination signal to the 3'-Poly(A) tail of mRNA. Direct association of erf3/GSPT with polyadenylate-binding protein. 1035 5

We have identified a homologue of the GTP-binding protein, Sar1p, in Plasmodium falciparum. Sar1p is a small GTPase that is thought to play a crucial role in trafficking of proteins between the endoplasmic reticulum and the Golgi. The P.falciparum SAR1 gene is located on chromosome 4 and comprises two exons separated by a 508 bp intron. The deduced amino acid sequence of PfSar1p (GenBank accession number AF104306) shows 71% similarity (58% identity) to Sar1p from Saccharomyces cerevisiae. Expression of PfSar1p in erythrocytic stages of P. falciparum was confirmed by sequencing of a tryptic peptide derived from a polypeptide excised from an SDS-polyacrylamide gel. A recombinant protein corresponding to approximately 70% of the PfSar1p sequence was used to raise antibodies. The affinity-purified antiserum recognised a protein with an apparent molecular weight of 23 K in Western blots of malaria-infected erythrocytes but not in uninfected erythrocytes. PfSar1p was shown to be largely insoluble in non-ionic detergent and a low ionic strength buffer. Confocal immunofluorescence microscopy of malaria-infected erythrocytes was used to show that PfSar1p is located near the periphery of the parasite in discrete compartments, which appear to be distinct from the parasite endoplasmic reticulum. In addition, PfSar1p appears to be exported to structures outside the parasite in the erythrocyte cytoplasm. The export of PfSar1p to the erythrocyte cytosol is inhibited by treatment with brefeldin A. This provides the first evidence that the malaria parasite is capable of elaborating components of the classical vesicle-mediated trafficking machinery outside the boundaries of its own plasma membrane.
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PMID:A homologue of Sar1p localises to a novel trafficking pathway in malaria-infected erythrocytes. 1047 98

The mammalian GTP-binding protein GSPT, whose carboxy-terminal sequence is homologous to the eukaryotic elongation factor EF1alpha, binds to the polypeptide chain releasing factor eRF1 to function as eRF3 in translation termination. However, the amino-terminal domain of GSPT, which contains a prion-like sequence, is not required for the binding. Instead, the amino-terminal domain is capable of binding to the carboxy-terminal domain of polyadenylate-binding protein (PABP), whose amino terminus is associating with the poly(A) tail of mRNAs, presumably for their stabilization. Interestingly, multimerization of PABP with poly(A), which is ascribed to the action of its carboxy-terminal domain, was completely inhibited by the interaction with the amino-terminal domain of GSPT. This may facilitate shortening of the poly(A) tail of mRNAs by an RNase. Thus, GSPT/eRF3 appears to function not only as a stimulator of eRF1 in the translation termination but also as an initiator of the mRNA degradation machinery. Further physiological and cell biological approaches will be necessary to show whether our current in vitro findings on GSPT/eRF3 indeed reflect its bifunctional properties in living cells.
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PMID:Novel function of the eukaryotic polypeptide-chain releasing factor 3 (eRF3/GSPT) in the mRNA degradation pathway. 1064 60

In a previous publication we identified a novel human GTP-binding protein that was related to DRG, a developmentally regulated GTP-binding protein from the central nervous system of mouse. Here we demonstrate that both the human and the mouse genome possess two closely related drg genes, termed drg1 and drg2. The two genes share 62% sequence identity at the nucleotide and 58% identity at the protein level. The corresponding proteins appear to constitute a separate family within the superfamily of the GTP-binding proteins. The DRG1 and the DRG2 mRNA are widely expressed in human and mouse tissues and show a very similar distribution pattern. The human drg1 gene is located on chromosome 22q12, the human drg2 gene on chromosome 17p12. Distantly related species including Caenorhabditis elegans, Schizosaccharomyces pombe and Saccharomyces cerevisiae also possess two drg genes. In contrast, the genomes of archaebacteria (Halobium, Methanococcus, Thermoplasma) harbor only one drg gene, while eubacteria do not seem to contain any. The high conservation of the polypeptide sequences between distantly related organisms indicates an important role for DRG1 and DRG2 in a fundamental pathway.
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PMID:DRG represents a family of two closely related GTP-binding proteins. 1076 May 81

The YWK-II cDNA, RSD-2, encoding a sperm membrane protein was isolated from a rat testis cDNA expression library. Using the RSD-2 insert in combination with rapid amplification of cDNA ends (RACE), the corresponding human gene was isolated from a human testis cDNA expression library. The human testis cDNA, HSD-2, is 3654 bp in length and contains an open reading frame of 763 codons. Hydropathicity analysis showed that the deduced polypeptide is a single strand transmembrane protein. The deduced polypeptide has partial homology with the amyloid precursor protein (APP) and high homology with the amyloid precursor homologue, APLP2/APPH. The YWK-II gene was mapped and assigned to human chromosome locus: 11q24-25. Northern blotting of various human tissue RNAs using the HSD-2 cDNA as a probe showed that the gene is transcribed ubiquitously. The cytoplasmic domain of HSD-2 was expressed in Escherichia coli. In-vitro studies showed that the recombinant polypeptide bound to a GTP-binding protein (G(o)) and was phosphorylated by protein kinase C and cdc2 kinase. In mammalian F11 cells, the recombinant polypeptide was found to be coupled to G(o). Thus, the YWK-II component has the characteristics of a G(o)-coupled receptor and may be involved in G(o)-mediated signal transduction pathway. Protein kinase C and cdc2 kinase may regulate this pathway in spermatozoa by phosphorylating the cytoplasmic domain of the YWK-II component.
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PMID:Expression and characterization of the human YWK-II gene, encoding a sperm membrane protein related to the alzheimer betaA4-amyloid precursorprotein. 1110 89

ADP-ribosylation factor 1 (Arf1) is a GTP-binding protein that regulates membrane traffic. This function of Arf1 is, at least in part, mediated by Arf1 x GTP binding to coat proteins such as coatomer, clathrin adaptor protein (AP) complexes 1 and 3, and gamma-adaptin homology-Golgi associated Arf-binding (GGA) proteins. Binding to Arf1 x GTP recruits these coat proteins to membranes, leading to the formation of transport vesicles. Whereas coatomer and the AP complexes are hetero-oligomers, GGAs are single polypeptide chains. Therefore, working with recombinant GGAs is straightforward compared to the other Arf1 effectors. Consequently, the GGAs have been used as a model for studying Arf1 interactions with effectors and as reagents to determine Arf1 x GTP levels in cells. In this chapter, we describe in vitro assays for analysis of GGA interaction with Arf1 x GTP and for determining intracellular Arf1 x GTP levels.
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PMID:In vitro assays of Arf1 interaction with GGA proteins. 1641 79

MicroRNA deregulation is a critical event in tumor initiation and progression. The down-regulation of microRNA-138 has been frequently observed in various cancers, including tongue squamous cell carcinoma (TSCC). Our previous studies suggest that deregulation of miR-138 is associated with the enhanced proliferation and invasion in TSCC cells. Here, we seek to identify the targets of miR-138 in TSCC, and explore their functional relevance in tumorigenesis. Our genome-wide expression profiling experiments identified a panel of 194 unique transcripts that were significantly down-regulated in TSCC cells transfected with miR-138. A comprehensive screening using six different sequence-based microRNA target prediction algorithms revealed that 51 out of these 194 down-regulated transcripts are potential direct targets for miR-138. These targets include: chloride channel, nucleotide-sensitive, 1A (CLNS1A), G protein alpha inhibiting activity polypeptide 2 (GNAI2), solute carrier family 20, member 1 (SLC20A1), eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), and Rho-related GTP-binding protein C (RhoC). GNAI2 is a known proto-oncogene that is involved in the initiation and progression of several different types of tumors. Direct targeting of miR-138 to two candidate binding sequences located in the 3'-untranslated region of GNAI2 mRNA was confirmed using luciferase reporter gene assays. Knockdown of miR-138 in TSCC cells enhanced the expression of GNAI2 at both mRNA and protein levels. In contrast, ectopic transfection of miR-138 reduced the expression of GNAI2, which, in consequence, led to reduced proliferation, cell cycle arrest and apoptosis. In summary, we identified a number of high-confident miR-138 target genes, including proto-oncogene GNAI2, which may play an important role in TSCC initiation and progression.
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PMID:Identification and experimental validation of G protein alpha inhibiting activity polypeptide 2 (GNAI2) as a microRNA-138 target in tongue squamous cell carcinoma. 2107 96


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