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801.
Two major functions of the Golgi apparatus (GA) are formation of complex glycans and sorting of proteins destined for various
subcellular compartments or secretion. To fulfill these tasks proper localization of the accessory proteins within the different
sub-compartments of the GA is crucial. Here we investigate structural determinants mediating transition of the two glycosyltransferases
β-1,4- galactosyltransferase 1 (gal-T1) and the α-1,3-fucosyltransferase 6 (fuc-T6) from the trans-Golgi cisterna to the trans-Golgi network (TGN). Upon treatment with the ionophore monensin both glycosyltransferases are found in TGN-derived swollen
vesicles, as determined by confocal fluorescence microscopy and density gradient fractionation. Both enzymes carry a signal
consisting of the amino acids E5P6 in gal-T1 and D2P3 in fuc-T6 necessary for the transition of these glycosyltransferases from the trans-Golgi cisterna to the TGN, but not for their steady state localization in the trans-Golgi cisterna.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 30 July 2008; received after revision 17 September 2008; accepted 29 September 2008 相似文献
802.
Zinc binding to peptide analogs of the structural zinc site in alcohol dehydrogenase: Implications for an entatic state 总被引:1,自引:0,他引:1
Bergman T Zhang K Palmberg C Jörnvall H Auld DS 《Cellular and molecular life sciences : CMLS》2008,65(24):4019-4027
Zinc binding to the peptide replica and analogs to residues 93–115 of horse liver alcohol dehydrogenase (ADH) was examined
by competition of the peptides and the chromophoric chelator 4-(2- pyridylazo)resorcinol for zinc and X-ray absorption fine
structure analysis of the zinc ligands. In the enzyme, zinc is coordinated by four Cys residues. In the peptide replica, zinc
is bound to three Cys and one His residue. A four-Cys zinc coordination is observed only when His is removed, leading to increased
zinc stability. ADH crystal structures reveal that the ε-amino group of the conserved residue Lys323 is within H-bond distance
of the backbone amide oxygens of residues 103, 105 and 108, likely stabilizing the zinc coordination in the enzyme. The peptide
data thus indicate structural strain and increased energy in the zinc-binding site in the protein, characteristic of an entatic
state, implying a functional nature for this zinc site.
Received 3 July 2008; received after revision 11 August 2008; accepted 1 September 2008 相似文献
803.
Loos RJ Lindgren CM Li S Wheeler E Zhao JH Prokopenko I Inouye M Freathy RM Attwood AP Beckmann JS Berndt SI;Prostate Lung Colorectal Ovarian 《Nature genetics》2008,40(6):768-775
To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits. 相似文献
804.
805.
The Pristionchus pacificus genome provides a unique perspective on nematode lifestyle and parasitism
Dieterich C Clifton SW Schuster LN Chinwalla A Delehaunty K Dinkelacker I Fulton L Fulton R Godfrey J Minx P Mitreva M Roeseler W Tian H Witte H Yang SP Wilson RK Sommer RJ 《Nature genetics》2008,40(10):1193-1198
Here we present a draft genome sequence of the nematode Pristionchus pacificus, a species that is associated with beetles and is used as a model system in evolutionary biology. With 169 Mb and 23,500 predicted protein-coding genes, the P. pacificus genome is larger than those of Caenorhabditis elegans and the human parasite Brugia malayi. Compared to C. elegans, the P. pacificus genome has more genes encoding cytochrome P450 enzymes, glucosyltransferases, sulfotransferases and ABC transporters, many of which were experimentally validated. The P. pacificus genome contains genes encoding cellulase and diapausin, and cellulase activity is found in P. pacificus secretions, indicating that cellulases can be found in nematodes beyond plant parasites. The relatively higher number of detoxification and degradation enzymes in P. pacificus is consistent with its necromenic lifestyle and might represent a preadaptation for parasitism. Thus, comparative genomics analysis of three ecologically distinct nematodes offers a unique opportunity to investigate the association between genome structure and lifestyle. 相似文献
806.
Kao WH Klag MJ Meoni LA Reich D Berthier-Schaad Y Li M Coresh J Patterson N Tandon A Powe NR Fink NE Sadler JH Weir MR Abboud HE Adler SG Divers J Iyengar SK Freedman BI Kimmel PL Knowler WC Kohn OF Kramp K Leehey DJ Nicholas SB Pahl MV Schelling JR Sedor JR Thornley-Brown D Winkler CA Smith MW Parekh RS;Family Investigation of Nephropathy Diabetes Research Group 《Nature genetics》2008,40(10):1185-1192
As end-stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans, we hypothesized that susceptibility alleles for ESRD have a higher frequency in the West African than the European gene pool. We carried out a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% CI = 0.39-0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.2 to 0.6) in the gene encoding nonmuscle myosin heavy chain type II isoform A (MYH9) were associated with two to four times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans. 相似文献
807.
Stacey SN Gudbjartsson DF Sulem P Bergthorsson JT Kumar R Thorleifsson G Sigurdsson A Jakobsdottir M Sigurgeirsson B Benediktsdottir KR Thorisdottir K Ragnarsson R Scherer D Rudnai P Gurzau E Koppova K Höiom V Botella-Estrada R Soriano V Juberías P Grasa M Carapeto FJ Tabuenca P Gilaberte Y Gudmundsson J Thorlacius S Helgason A Thorlacius T Jonasdottir A Blondal T Gudjonsson SA Jonsson GF Saemundsdottir J Kristjansson K Bjornsdottir G Sveinsdottir SG Mouy M Geller F Nagore E Mayordomo JI 《Nature genetics》2008,40(11):1313-1318
To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide SNP association study of 930 Icelanders with BCC and 33,117 controls. After analyzing 304,083 SNPs, we observed signals from loci at 1p36 and 1q42, and replicated these associations in additional sample sets from Iceland and Eastern Europe. Overall, the most significant signals were from rs7538876 on 1p36 (OR = 1.28, P = 4.4 x 10(-12)) and rs801114 on 1q42 (OR = 1.28, P = 5.9 x 10(-12)). The 1p36 locus contains the candidate genes PADI4, PADI6, RCC2 and ARHGEF10L, and the gene nearest to the 1q42 locus is the ras-homolog RHOU. Neither locus was associated with fair pigmentation traits that are known risk factors for BCC, and no risk was observed for melanoma. Approximately 1.6% of individuals of European ancestry are homozygous for both variants, and their estimated risk of BCC is 2.68 times that of noncarriers. 相似文献
808.
Richards JB Yuan X Geller F Waterworth D Bataille V Glass D Song K Waeber G Vollenweider P Aben KK Kiemeney LA Walters B Soranzo N Thorsteinsdottir U Kong A Rafnar T Deloukas P Sulem P Stefansson H Stefansson K Spector TD Mooser V 《Nature genetics》2008,40(11):1282-1284
We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 x 10(-14) for rs1160312). The one man in seven who harbors risk alleles at both 20p11.22 and AR (encoding the androgen receptor) has a sevenfold-increased odds of androgenic alopecia (OR = 7.12, P = 3.7 x 10(-15)). 相似文献
809.
High-throughput sequencing provides insights into genome variation and evolution in Salmonella Typhi 总被引:1,自引:0,他引:1
Holt KE Parkhill J Mazzoni CJ Roumagnac P Weill FX Goodhead I Rance R Baker S Maskell DJ Wain J Dolecek C Achtman M Dougan G 《Nature genetics》2008,40(8):987-993
Isolates of Salmonella enterica serovar Typhi (Typhi), a human-restricted bacterial pathogen that causes typhoid, show limited genetic variation. We generated whole-genome sequences for 19 Typhi isolates using 454 (Roche) and Solexa (Illumina) technologies. Isolates, including the previously sequenced CT18 and Ty2 isolates, were selected to represent major nodes in the phylogenetic tree. Comparative analysis showed little evidence of purifying selection, antigenic variation or recombination between isolates. Rather, evolution in the Typhi population seems to be characterized by ongoing loss of gene function, consistent with a small effective population size. The lack of evidence for antigenic variation driven by immune selection is in contrast to strong adaptive selection for mutations conferring antibiotic resistance in Typhi. The observed patterns of genetic isolation and drift are consistent with the proposed key role of asymptomatic carriers of Typhi as the main reservoir of this pathogen, highlighting the need for identification and treatment of carriers. 相似文献
810.