Role of Proinsulin Self-Association in Mutant INS Gene–Induced Diabetes of Youth
dc.contributor.author | Sun, Jinhong | |
dc.contributor.author | Xiong, Yi | |
dc.contributor.author | Li, Xin | |
dc.contributor.author | Haataja, Leena | |
dc.contributor.author | Chen, Wei | |
dc.contributor.author | Mir, Saiful A. | |
dc.contributor.author | Lv, Li | |
dc.contributor.author | Madley, Rachel | |
dc.contributor.author | Larkin, Dennis | |
dc.contributor.author | Anjum, Arfah | |
dc.contributor.author | Dhayalan, Balamurugan | |
dc.contributor.author | Rege, Nischay | |
dc.contributor.author | Wickramasinghe, Nalinda P. | |
dc.contributor.author | Weiss, Michael A. | |
dc.contributor.author | Itkin-Ansari, Pamela | |
dc.contributor.author | Kaufman, Randal J. | |
dc.contributor.author | Ostrov, David A. | |
dc.contributor.author | Arvan, Peter | |
dc.contributor.author | Liu, Ming | |
dc.contributor.department | Biochemistry and Molecular Biology, School of Medicine | en_US |
dc.date.accessioned | 2022-11-16T13:45:57Z | |
dc.date.available | 2022-11-16T13:45:57Z | |
dc.date.issued | 2020-05 | |
dc.description.abstract | Abnormal 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_US |
dc.eprint.version | Final published version | en_US |
dc.identifier.citation | Sun 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/db19-1106 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/30558 | |
dc.language.iso | en_US | en_US |
dc.publisher | American Diabetes Association | en_US |
dc.relation.isversionof | 10.2337/db19-1106 | en_US |
dc.relation.journal | Diabetes | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | Publisher | en_US |
dc.subject | Insulin | en_US |
dc.subject | Proinsulin | en_US |
dc.subject | Islets of Langerhans | en_US |
dc.subject | Protein Conformation | en_US |
dc.title | Role of Proinsulin Self-Association in Mutant INS Gene–Induced Diabetes of Youth | en_US |
dc.type | Article | en_US |