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Role of Proinsulin Self-Association in Mutant INS gene-induced Diabetes of Youth

By Jinhong Sun, Yi Xiong, Xin Li, Leena Haataja, Wei Chen, Saiful A Mir, Rachel Madley, Dennis Larkin, Arfah Anjum, Balamurugan Dhayalan, Nischay Rege, Nalinda D. Wickramasinghe, Michael A. Weiss, Pamela Itkin-Ansari, Randal J Kaufman, David A. Ostrov, Peter Arvan, Ming Liu

Posted 01 Oct 2019
bioRxiv DOI: 10.1101/786970 (published DOI: 10.2337/db19-1106)

Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin in the endoplasmic reticulum (ER) drive the molecular pathogenesis of Mutant-INS-gene induced Diabetes of Youth (MIDY). How these abnormal interactions are initiated remains unknown. Normally, proinsulin-WT dimerizes in the ER. Here, we suggest that the normal proinsulin-proinsulin contact surface, involving the B-chain, contributes to dominant-negative effects of misfolded MIDY mutants. Specifically, we find that proinsulin Tyr-B16, which is a key residue in normal proinsulin dimerization, helps confer dominant-negative behavior of MIDY mutant proinsulin-C(A7)Y. Substitutions of Tyr-B16 with ether Ala, Asp, or Pro in proinsulin-C(A7)Y each decrease the abnormal interactions between the MIDY mutant and proinsulin-WT, rescuing proinsulin-WT export, limiting ER stress, and increasing insulin production in b-cells and human islets. This study reveals the first evidence indicating that noncovalent proinsulin-proinsulin contact initiates dominant-negative behavior of misfolded proinsulin, pointing to a novel therapeutic target to enhance bystander proinsulin export for increased insulin production.

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