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J. Biol. Chem., Vol. 279, Issue 17, 17085-17089, April 23, 2004

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The Acetylcholinesterase Homology Region Is Essential for Normal Conformational Maturation and Secretion of Thyroglobulin^*

Young-nam Park and Peter Arvan

From the Division of Metabolism, Endocrinology, and Diabetes and the Program of Cellular and Molecular Biology, University of Michigan Medical Center, Ann Arbor, Michigan 48109

Secretion of thyroglobulin (Tg, a large homodimeric glycoprotein) is essential to deliver Tg to its site of iodination for thyroxine biosynthesis. An L2263P missense mutation in Tg has been proposed as the molecular defect causing congenital goitrous hypothyroidism in cog/cog mice due to perturbed Tg homodimerization, resulting in its retention within the endoplasmic reticulum. The mutation falls within a carboxyl-terminal region of Tg with high structural similarity to the entirety of acetylcholinesterase (AChE), a secretory protein that also forms homodimers. We provide new evidence that authentic AChE and the cholinesterase-like domain of Tg share a common tertiary structure. Moreover, we find that a Tg truncation, deleted of the cholinesterase-like region (but not a comparably sized deletion of internal Tg regions), blocks Tg export. Appending to this truncation a cDNA encoding authentic AChE results in translation of a chimeric protein in which AChE is present in a native, enzymatically active (albeit latent) conformation, and this fully rescues Tg secretion. Introduction of the cog mutation inhibits AChE enzyme activity, and established denaturing mutations of AChE block secretion of the Tg. Additional studies show that the native structure of the AChE region functions as a "dimerization domain," facilitating intracellular transport of Tg to the site of thyroid hormonogenesis.

Received for publication, December 22, 2003 , and in revised form, February 5, 2004.

^* This work was supported by National Institutes of Health Grant DK40344 (to P. A.). 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.

To whom correspondence should be addressed: Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, 5560 MSRB2, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0678. Tel.: 734-936-5006; Fax: 734-936-6684; E-mail: parvan{at}umich.edu.

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