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J. Biol. Chem., Vol. 280, Issue 14, 13209-13212, April 8, 2005

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Proinsulin Disulfide Maturation and Misfolding in the Endoplasmic Reticulum^*

Ming Liu, Yulin Li, Douglas Cavener, and Peter Arvan¶

From the Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109 and the Department of Biology, The Pennsylvania State University, University Park, Pennsylvania 16802

Upon nonreducing Tris-Tricine-urea-SDS-PAGE, newly synthesized proinsulin from pancreatic islets of normal rodents forms a band fast mobility representing the native disulfide isomer, which is efficiently secreted. In addition at least two slower migrating "isomer 1 and 2" bands are recovered, not discernible under reducing conditions, which represent minor species that exhibit less efficient secretion. Although rats and mice have two proinsulin genes, three distinct migrating species are also produced upon proinsulin expression from a single wild-type human proinsulin cDNA. The "Akita-type" proinsulin mutation, which causes dominant-negative diabetes mellitus due to point mutation C(A7)Y that leaves B7-cysteine without its disulfide pairing partner, is recovered as a form that near quantitatively co-migrates with the aberrant isomer 1 band of proinsulin. Anomalous migration is also demonstrated for several other mutants lacking a single cysteine. In islets from PERK^–/– mice, which exhibit premature loss of pancreatic beta cells, hypersynthesis of proinsulin increases the amount of nonnative proinsulin isomers. Such findings appear consistent with an hypothesis that supranormal production of nonnative proinsulin may predispose to pancreatic beta cell toxicity.

Received for publication, October 7, 2004 , and in revised form, February 7, 2005.

^* This work was supported by National Institutes of Health Grant DK 48280 and an American Diabetes Association mentor-based postdoctoral grant. 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 & Diabetes, University of Michigan Medical School, MSRB2 Rm. 5560, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0678. Tel.: 734-936-5505; Fax: 734-936-6684; E-mail: parvan{at}umich.edu.

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