Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood
Tobi, Elmar W. ; Slieker, Roderick C. ; Luijk, René ; Dekkers, Koen F. ; Stein, Aryeh D. ; Xu, Kate M. ; Slagboom, P.E. ; Zwet, Erik W. Van; Lumey, L.H. ; Heijmans, Bastiaan T. ; T'Hoen, Peter A. ; Pool, René ; Greevenbroek, Marleen M. Van; Stehouwer, Coen D. ; Kallen, Carla J. Van Der; Schalkwijk, Casper G. ; Wijmenga, Cisca ; Zhernakova, Sasha ; Tigchelaar, Ettje F. ; Beekman, Marian ; Deelen, Joris ; Heemst, Diana Van; Veldink, Jan H. ; Berg, Leonard H. Van Den; Duijn, Cornelia M. Van; Hofman, Albert ; Uitterlinden, André G. ; Jhamai, P.M. ; Verbiest, Michael ; Verkerk, Marijn ; Breggen, Ruud Van Der; Rooij, Jeroen Van; Lakenberg, Nico ; Mei, Hailiang ; Bot, Jan ; Zhernakova, Dasha V. ; Hof, Peter Van 't; Deelen, Patrick ; Nooren, Irene ; Moed, Matthijs ; Vermaat, Martijn ; Jan Bonder, Marc ; Dijk, Freerk Van; Arindrarto, Wibowo ; Kielbasa, Szymon M. ; Swertz, Morris A. ; Isaacs, Aaron ; Franke, Lude - \ 2018
Science Advances 4 (2018)1. - ISSN 2375-2548
Although it is assumed that epigenetic mechanisms, such as changes in DNA methylation (DNAm), underlie the relationship between adverse intrauterine conditions and adult metabolic health, evidence from human studies remains scarce. Therefore, we evaluated whether DNAm in whole blood mediated the association between prenatal famine exposure and metabolic health in 422 individuals exposed to famine in utero and 463 (sibling) controls. We implemented a two-step analysis, namely, a genome-wide exploration across 342, 596 cytosine-phosphate-guanine dinucleotides (CpGs) for potential mediators of the association between prenatal famine exposure and adult body mass index (BMI), serum triglycerides (TG), or glucose concentrations, which was followed by formalmediation analysis.DNAm mediated the association of prenatal famine exposure with adult BMI and TG but not with glucose. DNAm at PIM3 (cg09349128), a gene involved in energy metabolism, mediated 13.4% [95% confidence interval (CI), 5 to 28%] of the association between famine exposure and BMI. DNAm at six CpGs, including TXNIP (cg19693031), influencing b cell function, and ABCG1 (cg07397296), affecting lipid metabolism, together mediated 80% (95% CI, 38.5 to 100%) of the association between famine exposure and TG. Analyses restricted to those exposed to famine during early gestation identified additional CpGs mediating the relationship with TG near PFKFB3 (glycolysis) and METTL8 (adipogenesis). DNAm at the CpGs involved was associated with gene expression in an external data set and correlated with DNAm levels in fat depots in additional postmortem data. Our data are consistent with the hypothesis that epigenetic mechanisms mediate the influence of transient adverse environmental factors in early life on long-termmetabolic health. The specific mechanism awaits elucidation.
Habitual diet and diet quality in Irritable Bowel Syndrome: A case-control study
Tigchelaar, Ettje F. ; Mujagic, Zlatan ; Zhernakova, Alexandra ; Hesselink, M. ; Meijboom, S. ; Perenboom, C.W.M. ; Masclee, A.A.M. ; Wijmenga, Cisca ; Feskens, E.J.M. ; Jonkers, D. - \ 2017
Neurogastroenterology & Motility 29 (2017)12. - ISSN 1365-2982
Background Diet is considered to be a key factor in symptom generation in Irritable Bowel Syndrome (IBS) and patients tend to exclude food products from their diet in pursue of symptom relief, which may impair diet quality. Methods We evaluated habitual dietary intake in IBS patients with regard to nutrients and food products using an extensive food frequency questionnaire. One hundred ninety-four IBS patients were compared to 186 healthy controls using multiple logistic regression analysis. An overall diet quality score was calculated for each participant based on the criteria of the Dutch Healthy Diet (DHD) index. Key Results A lower DHD-score was found for IBS (mean [SD]: 52.9 [9.6]) vs controls (55.1 [9.2], P=.02). The diet of patients was lower in fibers (21 g vs 25 g per day, P=.002) and fructose (14 g vs 16 g, P=.033), while higher in total fat (37% vs 36% of total energy intake, P=.010) and added sugars (46 g vs 44 g, P=.029). Differences in daily intake of food products included lower consumption of apples (40 g vs 69 g, P<.001), pasta (28 vs 37 g, P=.029) and alcoholic beverages (130 g vs 193 g, P=.024) and higher consumption of processed meat (38 g vs 29 g, P<.001). Some of these findings correlated with gastrointestinal symptoms, showing differences between IBS subtypes. Conclusions and Inferences Differences in habitual diet were described, showing lower diet quality in IBS patients compared to controls, with increased consumption of fat and lower intake of fibers and fructose. Our data support the importance of personalized and professional nutritional guidance of IBS patients.
A novel biomarker panel for irritable bowel syndrome and the application in the general population
Mujagic, Zlatan ; Tigchelaar, Ettje F. ; Zhernakova, Alexandra ; Ludwig, Thomas ; Ramiro-Garcia, Javier ; Baranska, Agnieszka ; Swertz, Morris A. ; Masclee, A.A.M. ; Wijmenga, Cisca ; Schooten, Frederik J. Van; Smolinska, Agnieszka ; Jonkers, Daisy M.A.E. - \ 2016
Scientific Reports 6 (2016). - ISSN 2045-2322

Biological markers that measure gut health and diagnose functional gastro-intestinal (GI) disorders, such as irritable bowel syndrome (IBS), are lacking. The objective was to identify and validate a biomarker panel associated with the pathophysiology of IBS that discriminates IBS from healthy controls (HC), and correlates with GI symptom severity. In a case-control design, various plasma and fecal markers were measured in a cohort of 196 clinical IBS patients and 160 HC without GI symptoms. A combination of biomarkers, which best discriminates between IBS and HC was identified and validated in an independent internal validation set and by permutation testing. The correlation between the biomarker panel and GI symptom severity was tested in IBS patients and in a general population cohort of 958 subjects. A set of 8 biomarker panel was identified to discriminate IBS from HC with high sensitivity (88.1%) and specificity (86.5%). The results for the IBS subtypes were comparable. Moreover, a moderate correlation was found between the biomarker panel and GI symptom scores in the IBS (r = 0.59, p <0.001) and the general population cohorts (r = 0.51, p = 0.003). A novel multi-domain biomarker panel has been identified and validated, which correlated moderately to GI symptom severity in IBS and general population subjects.

Cohort profile: Lifelines DEEP, a prospective, general population cohort study in the northern Netherlands: study design and baseline characteristics
Tigchelaar, E.F. ; Zhernakova, A. ; Dekens, J.A.M. ; Hermes, G.D.A. ; Baranska, A. ; Mujagic, Z. ; Swertz, M.A. ; Munoz, A.M. ; Deelen, P. ; Cenit, M.C. ; Franke, L. ; Scholtens, S. ; Stolk, R.P. ; Wijmenga, C. ; Feskens, E.J.M. - \ 2015
BMJ Open 5 (2015). - ISSN 2044-6055 - 9 p.
Purpose There is a critical need for population-based prospective cohort studies because they follow individuals before the onset of disease, allowing for studies that can identify biomarkers and disease-modifying effects, and thereby contributing to systems epidemiology. Participants This paper describes the design and baseline characteristics of an intensively examined subpopulation of the LifeLines cohort in the Netherlands. In this unique subcohort, LifeLines DEEP, we included 1539 participants aged 18 years and older. Findings to date We collected additional blood (n=1387), exhaled air (n=1425) and faecal samples (n=1248), and elicited responses to gastrointestinal health questionnaires (n=1176) for analysis of the genome, epigenome, transcriptome, microbiome, metabolome and other biological levels. Here, we provide an overview of the different data layers in LifeLines DEEP and present baseline characteristics of the study population including food intake and quality of life. We also describe how the LifeLines DEEP cohort allows for the detailed investigation of genetic, genomic and metabolic variation for a wide range of phenotypic outcomes. Finally, we examine the determinants of gastrointestinal health, an area of particular interest to us that can be addressed by LifeLines DEEP. Future plans We have established a cohort of which multiple data levels allow for the integrative analysis of populations for translation of this information into biomarkers for disease, and which will offer new insights into disease mechanisms and prevention.
The Tip of the ‘‘Celiac Iceberg’’ in China: A Systematic Review and meta-Analysis
Yuan, J. ; Gao, J. ; Li, Xin ; Liu, F. ; Wijmenga, C. ; Chen, H. ; Gilissen, L.J.W.J. - \ 2013
PLoS ONE 8 (2013)12. - ISSN 1932-6203 - 14 p.
gene-frequencies - disease - wheat - prevalence - hla - populations - patient - people - risk
Methods - By searching the MEDLINE database and four Chinese full-text databases (CNKI, CBM, VIP and WANFANG) (up to August 2012), as well as two HLA allele frequency net databases and the Chinese Statistics Yearbook databases, we systematically reviewed the literature on definite and suspected cases of celiac disease, the predisposing HLA allele frequencies, and on gluten exposure in China. Meta-analysis was performed by analyzing DQ2, DQ8 and DQB1*0201 gene frequencies and heterogeneity in populations from different geographic regions and ethnicities in China. Results - At present, the number of reported celiac disease cases is extremely low in China. The frequencies of the HLA-DQ2.5 and HLA-DQ8 haplotypes were 3.4% (95% confidence interval 1.3–5.5%) and 2.1% (0.1–4.1%), respectively. HLA-DQ2 and HLA-DQ8 antigen frequencies were 18.4% (15.0–21.7%) and 8.0% (4.5–11.4%), respectively. The frequency of the DQB1*0201 allele was 10.5% (9.3–11.6%) and it was more common in the northern Chinese than in the southern Chinese populations. The chance of being exposed to gluten is rapidly increasing all over China nowadays. Conclusion - The data on HLA haplotyping, in conjunction with increasing wheat consumption, strongly suggests that the occurrence of celiac disease is more common in China than currently reported. Coordinated measures by the Chinese government, medical and agricultural research institutions, and food industries, would be justified to create more awareness about celiac disease and to prevent it becoming a medical and societal burden.
Exploring genetic determinants of plasma total cholesterol levels and their predictive value in a longitudinal study
Lu, Y. ; Feskens, E.J.M. ; Boer, J.M.A. ; Imholz, S. ; Verschuren, W.M.M. ; Wijmenga, C. ; Vaarhorst, A. ; Slagboom, E. ; Müller, M.R. ; Dollé, M.E.T. - \ 2010
Atherosclerosis 213 (2010)1. - ISSN 0021-9150 - p. 200 - 205.
density-lipoprotein cholesterol - heart-disease risk - cardiovascular-disease - apolipoprotein-e - lipid-levels - association - women - variants - reclassification - polymorphisms
BACKGROUND: Plasma total cholesterol (TC) levels are highly genetically determined. Although ample evidence of genetic determination of separate lipoprotein cholesterol levels has been reported, using TC level directly as a phenotype in a relatively large broad-gene based association study has not been reported to date. METHODS AND RESULTS: We genotyped 361 single nucleotide polymorphisms (SNPs) across 243 genes based on pathways potentially relevant to cholesterol metabolism in 3575 subjects that were examined thrice over 11 years. Twenty-three SNPs were associated with TC levels after adjustment for multiple testing. We used 12 of them (rs7412 and rs429358 in APOE, rs646776 in CELSR2, rs1367117 in APOB, rs6756629 in ABCG5, rs662799 in APOA5, rs688 in LDLR, rs10889353 in DOCK7, rs2304130 in NCAN, rs3846662 in HMGCR, rs2275543 in ABCA1, rs7275 in SMARCA4) that were confirmed in previous candidate association or genome-wide-association studies to define a gene risk score (GRS). Average TC levels increased from 5.23 ± 0.82 mmol/L for those with 11 or less cholesterol raising alleles to 6.03 ± 1.11 mmol/L for those with 18 or more (P for trend
Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes: a population-based cohort study
Berg, S.W. van den; Dolle, M.E.T. ; Imholz, S. ; A, D.L. van der; Slot, R. van 't; Wijmenga, C. ; Verschuren, W.M.M. ; Strien, C. ; Siezen, C.L.E. ; Hoebee, B. ; Feskens, E.J.M. ; Boer, J.M.A. - \ 2009
International Journal of Obesity 33 (2009)10. - ISSN 0307-0565 - p. 1143 - 1152.
genome-wide association - activated receptor-gamma - body-mass index - transcriptional regulation - postmenopausal women - waist circumference - apolipoprotein-e - polymorphisms - weight - metaanalysis
Background: As nuclear receptors and transcription factors have an important regulatory function in adipocyte differentiation and fat storage, genetic variation in these key regulators and downstream pathways may be involved in the onset of obesity. Objective: To explore associations between single nucleotide polymorphisms ( SNPs) in candidate genes from regulatory pathways that control fatty acid and glucose metabolism, and repeated measurements of body mass index (BMI) and waist circumference in a large Dutch study population. Methods: Data of 327 SNPs across 239 genes were analyzed for 3575 participants of the Doetinchem cohort, who were examined three times during 11 years, using the Illumina Golden Gate assay. Adjusted random coefficient models were used to analyze the relationship between SNPS and obesity phenotypes. False discovery rate q-values were calculated to account for multiple testing. Significance of the associations was defined as a q-value
Genetic susceptibility to respiratory syncytial virus bronchiolitis in preterm childeren is asosiated with airway remodeling genes and innate immune genes
Siezen, C.L.E. ; Hodemaekers, H.M. ; Ermers, M.J. ; Doornbos, G. ; Slot, R. van 't; Wijmenga, I.C. ; Houwelingen, H.C. ; Kimpen, J.L.L. ; Kimman, T.G. ; Hoebee, B. ; Janssen, R. - \ 2009
The Pediatric Infectious Disease Journal 28 (2009)4. - ISSN 0891-3668 - p. 333 - 335.
interferon signal-transduction - lung-function - asthma - polymorphisms - adam33 - disease - kinase
Prematurity is a risk factor for severe respiratory syncytial virus bronchiolitis. We show that genetic factors in innate immune genes (IFNA13, IFNAR2, STAT2, IL27, NFKBIA, C3, IL1RN, TLR5), in innate and adaptive immunity (IFNG), and in airway remodeling genes (ADAM33 and TGFBR1), affect disease susceptibility to a different extent in preterm children, born with underdeveloped lungs, than in term children
Upstream transcription factor 1 (USF1) in risk of type 2 diabetes: association study in 2000 Dutch Caucasians
Meex, S.J. ; Vliet-Ostaptchouk, J.V. ; Kallen, C.J.H. van der; Greevenbroek, M.M. ; Schalkwijk, C.G. ; Feskens, E.J.M. ; Blaak, E.E. ; Wijmenga, C. ; Hofker, M.H. ; Stehouwer, C.D. ; Bruin, T.W. - \ 2008
Molecular Genetics and Metabolism 94 (2008)3. - ISSN 1096-7192 - p. 352 - 355.
familial combined hyperlipidemia - genome-wide scan - provides independent replication - stimulatory factor-1 - susceptibility locus - chromosome 1q21-q24 - metabolic syndrome - glucose-intolerance - gene-gene - linkage
Type 2 diabetes shares substantial genetic and phenotypic overlap with familial combined hyperlipidemia. Upstream stimulatory factor 1 (USF1), a well-established susceptibility gene for familial combined hyperlipidemia, is postulated to be such a shared genetic determinant. We evaluated two established variants in familial combined hyperlipidemia (rs2073658 and rs3737787) for association with type 2 diabetes in two Dutch case-control samples (N = 2011). The first case-control sample comprised 501 subjects with type 2 diabetes from the Breda cohort and 920 healthy blood bank donors of Dutch Caucasian origin. The second case-control sample included 211 subjects with type 2 diabetes, and 379 normoglycemic controls. SNP rs2073658 and SNP rs3737787 were in perfect linkage disequilibrium. In the first case-control sample, prevalence of the major allele was higher in patients than in controls (75% versus 71%, OR = 1.25, p = 0.018). A similar effect-size and -direction was observed in the second case-control sample (76% versus 72%, OR = 1.22, p = 0.16). A combined analysis strengthened the evidence for association (OR = 1.23, p = 0.006). Notably, the increased risk for type 2 diabetes could be ascribed to the major allele, and its high frequency translated to a substantial population attributable risk of 14.5%.
Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations
Lu, Y. ; Dollé, M.E.T. ; Imholz, S. ; Slot, R. van 't; Verschuren, W.M.M. ; Wijmenga, C. ; Feskens, E.J.M. ; Boer, J.M.A. - \ 2008
Journal of Lipid Research 49 (2008). - ISSN 0022-2275 - p. 2582 - 2589.
nuclear receptor - hdl metabolism - association - expression - snps - risk - apolipoprotein - triglyceride - genome - lipids
The known genetic variants determining plasma HDL cholesterol (HDL-C) levels explain only part of its variation. Three hundred eighty-four single nucleotide polymorphisms (SNPs) across 251 genes based on pathways potentially relevant to HDL-C metabolism were selected and genotyped in 3,575 subjects from the Doetinchem cohort, which was examined thrice over 11 years. Three hundred fifty-three SNPs in 239 genes passed the quality-control criteria. Seven SNPs [rs1800777 and rs5882 in cholesteryl ester transfer protein (CETP); rs3208305, rs328, and rs268 in LPL; rs1800588 in LIPC; rs2229741 in NRIP1] were associated with plasma HDL-C levels with false discovery rate (FDR) adjusted q values (FDR_q) <0.05. Five other SNPs (rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, rs6060717 near SCAND1, and rs3213451 in MBTPS2 in women) were associated with plasma HDL-C levels with FDR_q between 0.05 and 0.2. Two less well replicated associations (rs3135506 in APOA5 and rs1800961 in HNF4A) known from the literature were also observed, but their significance disappeared after adjustment for multiple testing (P = 0.008, FDR_q = 0.221 for rs3135506; P = 0.018, FDR_q = 0.338 for rs1800961, respectively). In addition to replication of previous results for candidate genes (CETP, LPL, LIPC, HNF4A, and APOA5), we found interesting new candidate SNPs (rs2229741 in NRIP1, rs3213451 in MBTPS2, rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, and rs6060717 near SCAND1) for plasma HDL-C levels that should be evaluated further.
Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity-phenotypes: A population based cohort study
Berg, S.W. van den; Dolle, M.E.T. ; Imholz, S. ; Slot, R. van 't; Wijmenga, C. ; Verschuren, W.M.M. ; Hoebee, B. ; Feskens, E.J.M. ; Strien, C. ; Boer, J.M.A. - \ 2008
In: Proceedings of the 16th European Congress on Obesity, Geneva, Switzerland, 14-17 May 2008. - - p. S184 - S184.
Association of variants in upstream transcription factor 1 (USF1) with type 2 diabetes in the Dutch population
Meex, S.J.R. ; Vliet-Ostaptchouk, J.V. ; Kallen, C.J.H. van der; Greevenbroek, M.M.J. van; Schalkwijk, C.G. ; Feskens, E.J.M. ; Blaak, E.E. ; Haeften, T.W. van; Bruin, T.W.A. de; Wijmenga, C. ; Hofker, M.H. ; Stehouwer, C.D.A. - \ 2007
Diabetologia 50 (2007)Suppl.1. - ISSN 0012-186X - p. S511 - S511.
Association af variants in upstream transcription factor 1 (USF1) with type 2 diabetes in the Dutch population
Meex, S.J. ; Vliet-Ostaptchouk, J.V. ; Kallen, C.J.H. van der; Greevenbroek, M.M.J. van; Schalkwijk, C.G. ; Feskens, E.J.M. ; Blaak, E.E. ; Haeften, T.W. van; Bruin, T.W. ; Wijmenga, C. ; Hofker, M.H. ; Stehouwer, C.D. - \ 2007
Atherosclerosis Supplements 8 (2007)1. - ISSN 1567-5688 - p. 232 - 232.
Identification of TUB as a Novel Candidate Gene Influencing Body Weight in Humans
Shiri-Sverdlov, R. ; Custers, A. ; Vliet-Ostaptchouk, J.V. ; Gorp, P.J.J. van; Lindsey, P.J. ; Tilburg, J.H.O. van; Zhernakova, S. ; Feskens, E.J.M. ; A, D.L. van der; Dollé, M.E.T. ; Haeften, T.W. van; Koeleman, B.P.C. ; Hofker, M.H. ; Wijmenga, C. - \ 2006
Diabetes 55 (2006)2. - ISSN 0012-1797 - p. 385 - 389.
recessive mutations - obesity - population - protein - mouse - tulp1 - fat
Previously, we identified a locus on 11p influencing obesity in families with type 2 diabetes. Based on mouse studies, we selected TUB as a functional candidate gene and performed association studies to determine whether this controls obesity. We analyzed the genotypes of 13 single nucleotide polymorphisms (SNPs) around TUB in 492 unrelated type 2 diabetic patients with known BMI values. One SNP (rs1528133) was found to have a significant effect on BMI (1.54 kg/m2, P = 0.006). This association was confirmed in a population enriched for type 2 diabetes, using 750 individuals who were not selected for type 2 diabetes. Two SNPs in linkage disequilibrium with rs1528133 and mapping to the 3' end of TUB, rs2272382, and rs2272383 also affected BMI by 1.3 kg/m2 (P = 0.016 and P = 0.010, respectively). Combined analysis confirmed this association (P = 0.005 and P = 0.002, respectively). Moreover, comparing 349 obese subjects (BMI >30 kg/m2) from the combined cohort with 289 normal subjects (BMI
Gluten: a two-edged sword. Immunopathogenesis of celiac disease
Koning, F. de; Gilissen, L.J.W.J. ; Wijmenga, C. - \ 2005
Springer Seminars in Immunopathology 27 (2005)2. - ISSN 0344-4325 - p. 217 - 232.
t-cell epitope - small-intestinal mucosa - ctla4/cd28 gene region - wide linkage analysis - tissue transglutaminase - susceptibility loci - molecular characterization - binding characteristics - confers susceptibility - rheumatoid-arthritis
Celiac disease (CD) is a small intestinal disorder caused by adaptive and innate immune responses triggered by the gluten proteins present in wheat. In the intestine, gluten is partially degraded and modified, which results in gluten peptides that bind with high affinity to HLA-DQ2 or HLA-DQ8 and trigger an inflammatory T cell response. Simultaneously, gluten exposure leads to increased production of IL15, which induces the expression of NKG2D on intraepithelial lymphocytes and its ligand MICA on epithelial cells, leading to epithelial cell destruction. The gluten-specific T cell response results in the production of antibodies against tissue transglutaminase and these are specific indicators of disease. CD is one of the most common inherited diseases, the HLA-DQ locus being the major contributing genetic factor. However, as the inheritance does not follow a Mendelian segregation pattern, multiple other genes, each with relative weak effect, contribute to disease development. An important role for environmental factors, however, can not be ignored as the concordance rate in monozygous twins is considerably less than 100%. The identification of these environmental factors and susceptibility genes may allow a better understanding of disease etiology and provide diagnostic and prognostic markers. The current treatment for CD consists of a life-long gluten-free diet. Although long thought to be impossible, recent results suggest that the development of nontoxic wheat varieties may be feasible, which would aid disease prevention and provide an alternative food source for patients.
Probing solvent accessibility of transthyretin amyloid by solution NMR spectroscopy
Olofsson, A. ; Ippel, J.H. ; Wijmenga, S.S. ; Lundgren, E. ; Ohman, A. - \ 2004
Journal of Biological Chemistry 279 (2004)7. - ISSN 0021-9258 - p. 5699 - 5707.
hydrogen-exchange - tetramer dissociation - subunit interface - x-ray - fibrils - core - intermediate - proteins - variants - mutants
The human plasma protein transthyretin (TTR) may form fibrillar protein deposits that are associated with both inherited and idiopathic amyloidosis. The present study utilizes solution nuclear magnetic resonance spectroscopy, in combination with hydrogen/deuterium exchange, to determine residue-specific solvent protection factors within the fibrillar structure of the clinically relevant variant, TTRY114C. This novel approach suggests a fibril core comprised of the six beta-strands, A-B-E-F-G-H, which retains a native-like conformation. Strands C and D are dislocated from their native edge region and become solvent-exposed, leaving a new interface involving strands A and B open for intermolecular interactions. Our results further support a native-like intermolecular association between strands F-F' and H-H' with a prolongation of these beta-strands and, interestingly, with a possible shift in beta-strand register of the subunit assembly. This finding may explain previous observations of a monomeric intermediate preceding fibril formation. A structural model based on our results is presented.
Doubly sensitivity-enhanced 3D HCCH-TOCSY of 13C-labeled proteins in H2O using heteronuclear cross polarization and pulsed field gradients.
Wijmenga, S. ; Steensma, E. ; Mierlo, C.P.M. van - \ 1997
Journal of Magnetic Resonance 124 (1997). - ISSN 1090-7807 - p. 459 - 467.
Possible role of a short extra loop of the long-chain flavodoxin from Azotobacter chroococcum in electron transfer to nitrogenase: complete 1H, 15N and 13C backbone assignments and secondary solution structure of the flavodoxin.
Peelen, S. ; Wijmenga, S.S. ; Erbel, P.J.A. ; Robson, R.L. ; Eady, R.R. ; Vervoort, J. - \ 1996
Journal of biomolecular NMR 7 (1996). - ISSN 0925-2738 - p. 315 - 330.
Doubly sensitivity enhanced 3D TOCSY-HSQC.
Wijmenga, S.S. ; Mierlo, C.P.M. van; Steensma, E. - \ 1996
Journal of biomolecular NMR 8 (1996). - ISSN 0925-2738 - p. 319 - 330.
Three‐dimensional correlated NMR study of Megasphaera elsdenii flavodoxin in the oxidized state
Wijmenga, Sybren S. ; Mierlo, Carlo P.M. van - \ 1991
European Journal of Biochemistry 195 (1991)3. - ISSN 0014-2956 - p. 807 - 822.

The value of a three‐dimensional (3D) non‐selective total correlation/nuclear Overhauser enhancement spectroscopy (TOCSY‐NOESY) spectrum for making sequential resonance assignments in proteins is demonstrated using the relatively large Megasphaera elsdenii flavodoxin (molecular mass 15 kDa) in the oxidized state. An easy and concise method for the analysis of 3D‐NMR spectra and a strategy for the resonance assignment of 3D‐NMR protein spectra is introduced. In this context, non‐selective TOCSY‐NOESY is compared with selective TOCSY‐NOESY and non‐selective NOESY‐TOCSY. Sequential assignments in various secondary structure elements of flavodoxin are made using the method of analysis introduced. NOEs not previously identified in 2D‐NMR spectra due to resonance overlap are found in the 3D Clean‐TOCSY‐NOESY spectrum. Also additional side‐chain assignments could be made.

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