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The core cysteines, (C909) of islet antigen-2 and (C945) of islet antigen-2?, are crucial to autoantibody binding in type 1 diabetes.

ABSTRACT: Cysteines are thought integral to conformational epitopes of islet antigen-2 (IA-2) autoantibodies (IA-2A), possibly through disulfide bond formation. We therefore investigated which cysteines are critical to IA-2A binding in patients with newly diagnosed type 1 diabetes. All 10 cysteines in the intracellular domain of IA-2 were modified to serine by site-directed mutagenesis, and the effects of these changes on autoantibody binding in comparison with wild-type control were investigated by radiobinding assay. Mutation of the protein tyrosine phosphatase (PTP) core cysteine (C909) in IA-2 caused large reductions in autoantibody binding. In contrast, little or no reduction in binding was seen following substitution of the other cysteines. Modification of the core cysteine (C945) in IA-2? also greatly reduced autoantibody binding. Lysine substitution of glutamate-836 in IA-2 or glutamate-872 in IA-2? resulted in modest reductions in binding and identified a second epitope region. Binding to IA-2 PTP and IA-2? PTP was almost abolished by mutation of both the core cysteine and these glutamates. The core cysteine is key to the major PTP conformational epitope, but disulfide bonding contributes little to IA-2A epitope integrity. In most patients, at disease onset, >90% of antibodies binding to the PTP domain of IA-2 recognize just two epitope regions.

SUBMITTER: Elvers KT

PROVIDER: S-EPMC3526053 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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The core cysteines, (C909) of islet antigen-2 and (C945) of islet antigen-2β, are crucial to autoantibody binding in type 1 diabetes.

Elvers Karen T KT Geoghegan Ivey I Shoemark Debbie K DK Lampasona Vito V Bingley Polly J PJ Williams Alistair J K AJ

Diabetes 20120910 1

Cysteines are thought integral to conformational epitopes of islet antigen-2 (IA-2) autoantibodies (IA-2A), possibly through disulfide bond formation. We therefore investigated which cysteines are critical to IA-2A binding in patients with newly diagnosed type 1 diabetes. All 10 cysteines in the intracellular domain of IA-2 were modified to serine by site-directed mutagenesis, and the effects of these changes on autoantibody binding in comparison with wild-type control were investigated by radio ...[more]

PMID: 22966073

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Project description:BackgroundIslet autoantibodies occur in type 2 diabetes. Our study aimed to investigate the prevalence of positive islet autoimmunity in community patients with type 2 diabetes.MethodsA total of 495 community patients with type 2 diabetes were recruited using the method of cluster sampling in this cross-sectional study. Three islet autoantibodies including glutamic acid decarboxylase antibody (GADA), insulin autoantibody (IAA) and islet cell antibody (ICA) were measured, and clinical characteristics involved in those individuals were evaluated.ResultsThe positive rate of islet autoantibodies was 28.5% in total, while combinations of different autoantibodies were rarely seen. Compared with GADA-negative group, positive counterparts significantly tended to have lower levels of body mass index (BMI), waist-hip ratio (WHR), and urinary microalbumin (mALB) (P < 0.05). Adjusted for confounding factors, WHR, triglycerides (TG), and mALB seemed to be negative independent predictors of GADA (OR < 1, P < 0.05). Patients with positive IAA tended to receive insulin treatment (P < 0.0001). Besides, fasting blood glucose (FBG), serum levels of high-density lipoprotein cholesterol (HDL-CH), aspartate transaminase (AST), and ?-glutamyltransferase (GGT) were more likely to be higher in IAA positive subgroup in comparison with the negative counterparts. While after AST was adjusted by unconditional logistic regression analysis, history of insulin treatment, FBG, HDL-CH, and GGT were confirmed as positive predictors of IAA. Furthermore, in patients who were IAA positive, those treated with exogenous insulin tended to have longer duration of diabetes than non-insulin treatment counterparts (P < 0.0001). With regard to ICA, however, there were no significant differences between the two subgroups, except that serum level of AST/ALT seemed to be slightly different (P = 0.064).ConclusionThese data suggested that type 2 diabetic community patients with positive GADA tended to be lean and were able to maintain normal lipid metabolism, while patients with positivity of IAA were frequently accompanied with insulin treatment and more closely associated with diabetic liver damage.

Dataset Information

The core cysteines, (C909) of islet antigen-2 and (C945) of islet antigen-2?, are crucial to autoantibody binding in type 1 diabetes.

Publications

The core cysteines, (C909) of islet antigen-2 and (C945) of islet antigen-2β, are crucial to autoantibody binding in type 1 diabetes.

Similar Datasets

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