RELATIONSHIP OF THE 37,000-M(R) AND 40,000-M(R) TRYPTIC FRAGMENTS OF ISLET ANTIGENS IN INSULIN-DEPENDENT DIABETES TO THE PROTEIN-TYROSINE PHOSPHATASE-LIKE MOLECULE IA-2 (ICA512)

Sera from patients with insulin-dependent diabetes immunoprecipitate 6 4,000-M(r) proteins, distinct from glutamate decarboxylase, that are c leaved to 37,000- and 40,000-M(r) fragments by trypsin. We investigate d possible relationships between 37,000- or 40,000-M(r) fragments of a ntigen and the tyrosine phosphatase-like protein, IA-2 (ICA512). Antib odies from nondiabetic relatives bound differentially to 37,000- and 4 0,000-M(r) fragments indicating presence of distinct epitopes, Precurs ors of these fragments could be separated on immobilized lectins, sugg esting different carbohydrate content. Levels of antibodies to 40,000- M(r) fragments were strongly associated with those to the intracellula r domain of IA-2. Recombinant intracellular domain of IA-2 blocked bin ding of antibodies to 40,000-M(r) fragments expressed by insulinoma ce lls and partially blocked binding to 37,000-M(r) fragments. Furthermor e, trypsinization of recombinant intracellular domain of IA-2 generate d proteolytic fragments of identical M(r) to the 40,000-M(r) fragments of insulinoma antigen; 37,000-M(r) fragments were not generated. Thus , 40,000-M(r) fragments of islet autoantigen are derived from a protei n similar or identical to the tyrosine phosphatase-like molecule, IA-2 . The 37,000-M(r) fragments are derived from a different, although rel ated, protein.