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Identification of a Second Transmembrane Protein Tyrosine Phosphatase, IA-2β , as an Autoantigen in Insulin-Dependent Diabetes Mellitus: Precursor of the 37-kDa Tryptic Fragment
Jia Lu, Qing Li, Hong Xie, Zhi-Jian Chen, Anna E. Borovitskaya, Noel K. Maclaren, Abner Louis Notkins and Michael S. Lan
Proceedings of the National Academy of Sciences of the United States of America
Vol. 93, No. 6 (Mar. 19, 1996), pp. 2307-2311
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/38668
Page Count: 5
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A novel cDNA, IA-2β , was isolated from a mouse neonatal brain library. The predicted protein sequence revealed an extracellular domain, a transmembrane region, and an intracellular domain. The intracellular domain is 376 amino acids long and 74% identical to the intracellular domain of IA-2, a major autoantigen in insulin-dependent diabetes mellitus (IDDM). A partial sequence of the extracellular domain of IA-2β indicates that it differs substantially (only 26% identical) from that of IA-2. Both molecules are expressed in islets and brain tissue. Forty-six percent (23 of 50) of the IDDM sera but none of the sera from normal controls (0 of 50) immunoprecipitated the intracellular domain of IA-2β . Competitive inhibition experiments showed that IDDM sera have autoantibodies that recognize both common and distinct determinants on IA-2 and IA-2β . Many IDDM sera are known to immunoprecipitate 37-kDa and 40-kDa tryptic fragments from islet cells, but the identity of the precursor protein(s) has remained elusive. The current study shows that treatment of recombinant IA-2β and IA-2 with trypsin yields a 37-kDa fragment and a 40-kDa fragment, respectively, and that these fragments can be immunoprecipitated with diabetic sera. Absorption of diabetic sera with unlabeled recombinant IA-2 or IA-2β , prior to incubation with radiolabeled 37-kDa and 40-kDa tryptic fragments derived from insulinoma or glucagonoma cells, blocks the immunoprecipitation of both of these radiolabeled tryptic fragments. We conclude that IA-2β and IA-2 are the precursors of the 37-kDa and 40-kDa islet cell autoantigens, respectively, and that both IA-2 and IA-2β are major autoantigens in IDDM.
Proceedings of the National Academy of Sciences of the United States of America © 1996 National Academy of Sciences