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J. Biol. Chem., Vol. 283, Issue 8, 4674-4681, February 22, 2008

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Structure of the Mature Ectodomain of the Human Receptor-type Protein-tyrosine Phosphatase IA-2^*

María E. Primo, Sebastián Klinke^¶, Mauricio P. Sica^||, Fernando A. Goldbaum^¶, Jean Jakoncic^**, Edgardo Poskus, and Mario R. Ermácora^||1

From the Consejo Nacional de Investigaciones Científicas y Técnicas (Conicet), Rivadavia 1917 C1033AAJ, Ciudad Autónoma de Buenos Aires, Argentina, the Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires (UBA) and Idehu (Conicet-UBA), Junín 954, C1113AAD, Ciudad Autónoma de Buenos Aires, Argentina, the ^¶Fundación Instituto Leloir, IIBBA-Conicet, Patricias Argentinas 435, C1405BWE, Ciudad Autónoma de Buenos Aires, Argentina, the ^||Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Roque Sáenz Peña 352, B1876BXD Bernal, Buenos Aires, Argentina, and the ^**National Synchrotron Light Source, Brookhaven National Laboratory, Upton, New York 11973-5000

IA-2 (insulinoma-associated protein 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 1.30Å resolution. The fold of meIA-2 is related to the SEA (sea urchin sperm protein, enterokinase, agrin)) domains of mucins, suggesting its participation in adhesive contacts to the extracellular matrix and providing clues on how this kind of molecule 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.

Received for publication, October 1, 2007 , and in revised form, November 19, 2007.

^* This work was supported by grants from Conicet, Universidad Nacional de Quilmes, Universidad de Buenos Aires, and Agencia Nacional de Promoción Científica y Tecnológica. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 2QT7) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The on-line version of this article (available at http://www.jbc.org) contains two figures and two data files.

¹ To whom correspondence should be addressed. Tel.: 54-114-365-7100, Argentina. E-mail: ermacora{at}unq.edu.ar.

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