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排序方式: 共有105条查询结果,搜索用时 15 毫秒
61.
Bocquet N Prado de Carvalho L Cartaud J Neyton J Le Poupon C Taly A Grutter T Changeux JP Corringer PJ 《Nature》2007,445(7123):116-119
Ligand-gated ion channels (LGICs) mediate excitatory and inhibitory transmission in the nervous system. Among them, the pentameric or 'Cys-loop' receptors (pLGICs) compose a family that until recently was found in only eukaryotes. Yet a recent genome search identified putative homologues of these proteins in several bacterial species. Here we report the cloning, expression and functional identification of one of these putative homologues from the cyanobacterium Gloeobacter violaceus. It was expressed as a homo-oligomer in HEK 293 cells and Xenopus oocytes, generating a transmembrane cationic channel that is opened by extracellular protons and shows slow kinetics of activation, no desensitization and a single channel conductance of 8 pS. Electron microscopy and cross-linking experiments of the protein fused to the maltose-binding protein and expressed in Escherichia coli are consistent with a homo-pentameric organization. Sequence comparison shows that it possesses a compact structure, with the absence of the amino-terminal helix, the canonical disulphide bridge and the large cytoplasmic domain found in eukaryotic pLGICs. Therefore it embodies a minimal structure required for signal transduction. These data establish the prokaryotic origin of the family. Because Gloeobacter violaceus carries out photosynthesis and proton transport at the cytoplasmic membrane, this new proton-gated ion channel might contribute to adaptation to pH change. 相似文献
62.
Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about resistance to infection and silencing or tolerance to self. In the settings of infection and cancer, microbes and tumours can exploit DCs to evade immunity, but DCs also can generate resistance, a capacity that is readily enhanced with DC-targeted vaccines. During allergy, autoimmunity and transplant rejection, DCs instigate unwanted responses that cause disease, but, again, DCs can be harnessed to silence these conditions with novel therapies. Here we present some medical implications of DC biology that account for illness and provide opportunities for prevention and therapy. 相似文献
63.
Kornum BR Kawashima M Faraco J Lin L Rico TJ Hesselson S Axtell RC Kuipers H Weiner K Hamacher A Kassack MU Han F Knudsen S Li J Dong X Winkelmann J Plazzi G Nevsimalova S Hong SC Honda Y Honda M Högl B Ton TG Montplaisir J Bourgin P Kemlink D Huang YS Warby S Einen M Eshragh JL Miyagawa T Desautels A Ruppert E Hesla PE Poli F Pizza F Frauscher B Jeong JH Lee SP Strohl KP Longstreth WT Kvale M Dobrovolna M Ohayon MM Nepom GT Wichmann HE Rouleau GA Gieger C Levinson DF Gejman PV Meitinger T 《Nature genetics》2011,43(1):66-71
Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y?? gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10?1?, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases. 相似文献
64.
Guernsey DL Matsuoka M Jiang H Evans S Macgillivray C Nightingale M Perry S Ferguson M LeBlanc M Paquette J Patry L Rideout AL Thomas A Orr A McMaster CR Michaud JL Deal C Langlois S Superneau DW Parkash S Ludman M Skidmore DL Samuels ME 《Nature genetics》2011,43(4):360-364
Meier-Gorlin syndrome is a rare autosomal recessive genetic condition whose primary clinical hallmarks include small stature, small external ears and small or absent patellae. Using marker-assisted mapping in multiple families from a founder population and traditional coding exon sequencing of positional candidate genes, we identified three different mutations in the gene encoding ORC4, a component of the eukaryotic origin recognition complex, in five individuals with Meier-Gorlin syndrome. In two such individuals that were negative for mutations in ORC4, we found potential mutations in ORC1 and CDT1, two other genes involved in origin recognition. ORC4 is well conserved in eukaryotes, and the yeast equivalent of the human ORC4 missense mutation was shown to be pathogenic in functional assays of cell growth. This is the first report, to our knowledge, of a germline mutation in any gene of the origin recognition complex in a vertebrate organism. 相似文献
65.
Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile 总被引:1,自引:0,他引:1
Kilpeläinen TO Zillikens MC Stančákova A Finucane FM Ried JS Langenberg C Zhang W Beckmann JS Luan J Vandenput L Styrkarsdottir U Zhou Y Smith AV Zhao JH Amin N Vedantam S Shin SY Haritunians T Fu M Feitosa MF Kumari M Halldorsson BV Tikkanen E Mangino M Hayward C Song C Arnold AM Aulchenko YS Oostra BA Campbell H Cupples LA Davis KE Döring A Eiriksdottir G Estrada K Fernández-Real JM Garcia M Gieger C Glazer NL Guiducci C Hofman A Humphries SE Isomaa B Jacobs LC Jula A Karasik D Karlsson MK 《Nature genetics》2011,43(8):753-760
Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ~2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance. 相似文献
66.
Crow YJ Hayward BE Parmar R Robins P Leitch A Ali M Black DN van Bokhoven H Brunner HG Hamel BC Corry PC Cowan FM Frints SG Klepper J Livingston JH Lynch SA Massey RF Meritet JF Michaud JL Ponsot G Voit T Lebon P Bonthron DT Jackson AP Barnes DE Lindahl T 《Nature genetics》2006,38(8):917-920
Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1(-/-) mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response. 相似文献
67.
van der Burg M van Zelm MC Driessen GJ van Dongen JJ 《Cellular and molecular life sciences : CMLS》2012,69(1):59-73
Primary antibody deficiencies (PAD) form the largest group of inherited disorders of the immune system. They are characterized
by a marked reduction or absence of serum immunoglobulins (Ig) due to disturbed B cell differentiation and by a poor response
to vaccination. PAD can be divided into agammaglobulinemia, Ig class switch recombination deficiencies, and idiopathic hypogammaglobulinemia.
Over the past 20 years, defects have been identified in 18 different genes, but in many PAD patients the underlying gene defects
have not been found. Diagnosis of known PAD and discovery of new PAD is important for good patient care. In this review, we
present the effects of genetic defects in the context of normal B cell differentiation, and we discuss how new technical developments
can support understanding and discovering new genetic defects in PAD. 相似文献
68.
Uusi-Rauva K Kyttälä A van der Kant R Vesa J Tanhuanpää K Neefjes J Olkkonen VM Jalanko A 《Cellular and molecular life sciences : CMLS》2012,69(12):2075-2089
CLN3 is an endosomal/lysosomal transmembrane protein mutated in classical juvenile onset neuronal ceroid lipofuscinosis, a fatal inherited neurodegenerative lysosomal storage disorder. The function of CLN3 in endosomal/lysosomal events has remained elusive due to poor understanding of its interactions in these compartments. It has previously been shown that the localisation of late endosomal/lysosomal compartments is disturbed in cells expressing the most common disease-associated CLN3 mutant, CLN3?ex7-8 (c.462-677del). We report here that a protracted disease causing mutant, CLN3E295K, affects the properties of late endocytic compartments, since over-expression of the CLN3E295K mutant protein in HeLa cells induced relocalisation of Rab7 and a perinuclear clustering of late endosomes/lysosomes. In addition to the previously reported disturbances in the endocytic pathway, we now show that the anterograde transport of late endosomal/lysosomal compartments is affected in CLN3 deficiency. CLN3 interacted with motor components driving both plus and minus end microtubular trafficking: tubulin, dynactin, dynein and kinesin-2. Most importantly, CLN3 was found to interact directly with active, guanosine-5'-triphosphate (GTP)-bound Rab7 and with the Rab7-interacting lysosomal protein (RILP) that anchors the dynein motor. The data presented in this study provide novel insights into the role of CLN3 in late endosomal/lysosomal membrane transport. 相似文献
69.
Weedon MN Lango H Lindgren CM Wallace C Evans DM Mangino M Freathy RM Perry JR Stevens S Hall AS Samani NJ Shields B Prokopenko I Farrall M Dominiczak A;Diabetes Genetics Initiative;Wellcome Trust Case Control Consortium Johnson T Bergmann S Beckmann JS Vollenweider P Waterworth DM Mooser V Palmer CN Morris AD Ouwehand WH;Cambridge GEM Consortium Zhao JH Li S Loos RJ Barroso I Deloukas P Sandhu MS Wheeler E Soranzo N Inouye M Wareham NJ Caulfield M Munroe PB Hattersley AT McCarthy MI Frayling TM 《Nature genetics》2008,40(5):575-583
Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait. 相似文献
70.
A Pichlmair K Kandasamy G Alvisi O Mulhern R Sacco M Habjan M Binder A Stefanovic CA Eberle A Goncalves T Bürckstümmer AC Müller A Fauster C Holze K Lindsten S Goodbourn G Kochs F Weber R Bartenschlager AG Bowie KL Bennett J Colinge G Superti-Furga 《Nature》2012,487(7408):486-490
Viruses must enter host cells to replicate, assemble and propagate. Because of the restricted size of their genomes, viruses have had to evolve efficient ways of exploiting host cell processes to promote their own life cycles and also to escape host immune defence mechanisms. Many viral open reading frames (viORFs) with immune-modulating functions essential for productive viral growth have been identified across a range of viral classes. However, there has been no comprehensive study to identify the host factors with which these viORFs interact for a global perspective of viral perturbation strategies. Here we show that different viral perturbation patterns of the host molecular defence network can be deduced from a mass-spectrometry-based host-factor survey in a defined human cellular system by using 70 innate immune-modulating viORFs from 30 viral species. The 579 host proteins targeted by the viORFs mapped to an unexpectedly large number of signalling pathways and cellular processes, suggesting yet unknown mechanisms of antiviral immunity. We further experimentally verified the targets heterogeneous nuclear ribonucleoprotein?U, phosphatidylinositol-3-OH kinase, the WNK (with-no-lysine) kinase family and USP19 (ubiquitin-specific peptidase 19) as vulnerable nodes in the host cellular defence system. Evaluation of the impact of viral immune modulators on the host molecular network revealed perturbation strategies used by individual viruses and by viral classes. Our data are also valuable for the design of broad and specific antiviral therapies. 相似文献