Structure of the mature ectodomain of the human receptor-type protein-tyrosine phosphatase IA-2

PRIMO, M. E., KLINKE, S., SICA, M. P., GOLDBAUM, F. A., JAKONCIC, J., POSKUS, E. AND ERMÁCORA, M. R.

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Año: 2008 vol. 238 p. 4674 - 4681

0021-9258

IA-2 is a protein-tyrosine phosphatase receptor located in secretory granules of neuroendocrine cells. Initially, it attracted attention due to its involvement in the autoimmune response associated to diabetes. Later it was found that upon exocytosis, the cytoplasmic domain of IA-2 is cleaved and relocated to the nucleus, where it enhances the transcription of the insulin gene. A concerted functioning of the whole receptor is to be expected. However, very little is known about the structure and function of the transmembrane and extracellular domains of IA-2. To address this issue, we solved the X-ray structure of the mature ectodomain of IA-2 (meIA-2) to 1.30 Å resolution. The fold of meIA-2 is related to the SEA domains of mucins, suggesting its participation in adhesive contacts to the extracellular matrix, and providing clues on how this kind of molecules may associate and form homo- and heterodimers. Moreover, we discovered that meIA-2 is self proteolyzed in vitro by reactive oxygen species, suggesting the possibility of a new shedding mechanism that might be significant in normal function or pathological processes. Knowledge of meIA-2 structure should facilitate the search of its possible ligands and molecular interactions.