Sun, JinhongXiong, YiLi, XinHaataja, LeenaChen, WeiMir, Saiful A.Lv, LiMadley, RachelLarkin, DennisAnjum, ArfahDhayalan, BalamuruganRege, NischayWickramasinghe, Nalinda P.Weiss, Michael A.Itkin-Ansari, PamelaKaufman, Randal J.Ostrov, David A.Arvan, PeterLiu, Ming2022-11-162022-11-162020-05Sun J, Xiong Y, Li X, et al. Role of Proinsulin Self-Association in Mutant INS Gene-Induced Diabetes of Youth. Diabetes. 2020;69(5):954-964. doi:10.2337/db19-1106https://hdl.handle.net/1805/30558Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin (PI) 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, PI-WT dimerizes in the ER. Here, we suggest that the normal PI-PI contact surface, involving the B-chain, contributes to dominant-negative effects of misfolded MIDY mutants. Specifically, we find that PI B-chain tyrosine-16 (Tyr-B16), which is a key residue in normal PI dimerization, helps confer dominant-negative behavior of MIDY mutant PI-C(A7)Y. Substitutions of Tyr-B16 with either Ala, Asp, or Pro in PI-C(A7)Y decrease the abnormal interactions between the MIDY mutant and PI-WT, rescuing PI-WT export, limiting ER stress, and increasing insulin production in β-cells and human islets. This study reveals the first evidence indicating that noncovalent PI-PI contact initiates dominant-negative behavior of misfolded PI, pointing to a novel therapeutic target to enhance PI-WT export and increase insulin production.en-USPublisher PolicyInsulinProinsulinIslets of LangerhansProtein ConformationArticle