Role of Proinsulin Self-Association in Mutant INS Gene–Induced Diabetes of Youth
| Autor: | Pamela Itkin-Ansari, Peter Arvan, Nalinda P. Wickramasinghe, Saiful A. Mir, Arfah Anjum, Michael A. Weiss, Xin Li, Leena Haataja, Yi Xiong, Nischay Rege, Li Lv, Wei Chen, David A. Ostrov, Randal J. Kaufman, Balamurugan Dhayalan, Rachel Madley, Dennis Larkin, Ming Liu, Jinhong Sun |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Mutation Chemistry Endocrinology Diabetes and Metabolism Endoplasmic reticulum Insulin medicine.medical_treatment Mutant 030209 endocrinology & metabolism medicine.disease_cause Cell biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Protein structure Cell culture Internal Medicine medicine Unfolded protein response Proinsulin |
| Zdroj: | Diabetes. 69:954-964 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db19-1106 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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